11-694992-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_021008.4(DEAF1):c.56T>C(p.Val19Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,061,004 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V19L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 3 hom. )

Consequence

DEAF1
NM_021008.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 0.125

Publications

1 publications found

Variant links:

Genes affected

DEAF1 (HGNC:14677): (DEAF1 transcription factor) This gene encodes a zinc finger domain-containing protein that functions as a regulator of transcription. The encoded proteins binds to its own promoter as well as to that of several target genes. Activity of this protein is important in the regulation of embryonic development. Mutations in this gene have been found in individuals with autosomal dominant cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

DEAF1 links:

EPS8L2 (HGNC:21296): (EPS8 signaling adaptor L2) This gene encodes a member of the EPS8 gene family. The encoded protein, like other members of the family, is thought to link growth factor stimulation to actin organization, generating functional redundancy in the pathways that regulate actin cytoskeletal remodeling. [provided by RefSeq, Dec 2008]

EPS8L2 Gene-Disease associations (from GenCC):

hearing loss, autosomal recessive 106
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

EPS8L2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024220645).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00122 (177/144622) while in subpopulation EAS AF = 0.0019 (8/4216). AF 95% confidence interval is 0.00148. There are 0 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEAF1	NM_021008.4 link	c.56T>C	p.Val19Ala	missense_variant	Exon 1 of 12	ENST00000382409.4	NP_066288.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEAF1	ENST00000382409.4 link	c.56T>C	p.Val19Ala	missense_variant	Exon 1 of 12	1	NM_021008.4	ENSP00000371846.3

Frequencies

GnomAD3 genomes

AF:

0.00123

AC:

177

AN:

144464

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000828

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000896

Gnomad ASJ

AF:

0.000293

Gnomad EAS

AF:

0.00189

Gnomad SAS

AF:

0.000257

Gnomad FIN

AF:

0.000428

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00174

Gnomad OTH

AF:

0.000985

GnomAD2 exomes

AF:

0.000972

AC:

AN:

28818

AF XY:

0.000861

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000354

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000718

Gnomad NFE exome

AF:

0.00157

Gnomad OTH exome

AF:

0.00128

GnomAD4 exome

AF:

0.00193

AC:

1769

AN:

916382

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

850

AN XY:

439298

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

17124

American (AMR)

AF:

0.00119

AC:

AN:

5062

Ashkenazi Jewish (ASJ)

AF:

0.000609

AC:

AN:

9852

East Asian (EAS)

AF:

0.00124

AC:

AN:

11248

South Asian (SAS)

AF:

0.000664

AC:

AN:

25598

European-Finnish (FIN)

AF:

0.00213

AC:

AN:

7052

Middle Eastern (MID)

AF:

0.000479

AC:

AN:

2088

European-Non Finnish (NFE)

AF:

0.00205

AC:

1649

AN:

806308

Other (OTH)

AF:

0.00131

AC:

AN:

32050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

144

217

289

361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

240

320

400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00122

AC:

177

AN:

144622

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

70488

show subpopulations

African (AFR)

AF:

0.000825

AC:

AN:

39978

American (AMR)

AF:

0.000894

AC:

AN:

14538

Ashkenazi Jewish (ASJ)

AF:

0.000293

AC:

AN:

3410

East Asian (EAS)

AF:

0.00190

AC:

AN:

4216

South Asian (SAS)

AF:

0.000256

AC:

AN:

3904

European-Finnish (FIN)

AF:

0.000428

AC:

AN:

9350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00174

AC:

115

AN:

66000

Other (OTH)

AF:

0.000976

AC:

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00213

Hom.:

Bravo

AF:

0.00118

ExAC

AF:

0.0000691

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 19 of the DEAF1 protein (p.Val19Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with DEAF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 434935). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DEAF1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DEAF1: BS2

May 10, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:1

Jan 22, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Intellectual disability-epilepsy-extrapyramidal syndrome

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DEAF1 p.V19A variant was identified in the literature as a somatic variant in a tumor sample from a patient with Biliary Tract Cancer (Yoon_2018_PMID:30602096). The variant was identified in dbSNP (ID: rs767318857) and ClinVar (classified as uncertain significance by University of Chicago, Genetic Services Laboratory). The variant was identified in control databases in 72 of 57852 chromosomes at a frequency of 0.001245, and was observed at the highest frequency in the European (non-Finnish) population in 50 of 27362 chromosomes (freq: 0.001827) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.V19 residue is not highly conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

Intellectual disability, autosomal dominant 24

Uncertain:1

Sep 07, 2023

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence variant is a single nucleotide substitution (T>C) at position 56 of the coding sequence of the DEAF1 gene that results in a valine to alanine amino acid change at residue 19 of the DEAF1 transcription factor protein. This is a previously reported variant (ClinVar) that has not been observed in individuals with DEAF1-related illness, to our knowledge. This variant is present in 72 of 57852 alleles (0.1245%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this Val to Ala amino acid change would be neutral, and the Val19 residue at this position is moderately conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this to be a variant of uncertain significance. ACMG Criteria: BP4, PM2

DEAF1-related disorder

Benign:1

Aug 30, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.11

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.40

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.024

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.0

PhyloP100

0.13

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

0.31

REVEL

Benign

0.076

Sift

Benign

0.50

Sift4G

Benign

0.50

Vest4

0.15

ClinPred

0.021

GERP RS

1.3

PromoterAI

0.0070

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.062

gMVP

0.22

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over