11-694992-A-G

Position:

• chr11-694992-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: DEAF1 NM_021008.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6 B:1
• Conservation: PhyloP100: 0.125

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]

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]

DEAF1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEAF1	NM_021008.4	c.56T>C	p.Val19Ala	missense_variant	1/12	ENST00000382409.4	NP_066288.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEAF1	ENST00000382409.4	c.56T>C	p.Val19Ala	missense_variant	1/12	1	NM_021008.4	ENSP00000371846.3

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 177 AN: 144464 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000972 AC: 28 AN: 28818 Hom.: 0 AF XY: 0.000861 AC XY: 16 AN XY: 18584

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 SAS exome AF: 0.000543

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.: 3 Cov.: 33 AF XY: 0.00193 AC XY: 850 AN XY: 439298

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.000609

Gnomad4 EAS exome AF: 0.00124

Gnomad4 SAS exome AF: 0.000664

Gnomad4 FIN exome AF: 0.00213

Gnomad4 NFE exome AF: 0.00205

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00122 AC: 177 AN: 144622 Hom.: 0 Cov.: 32 AF XY: 0.00125 AC XY: 88 AN XY: 70488

Gnomad4 AFR AF: 0.000825

Gnomad4 AMR AF: 0.000894

Gnomad4 ASJ AF: 0.000293

Gnomad4 EAS AF: 0.00190

Gnomad4 SAS AF: 0.000256

Gnomad4 FIN AF: 0.000428

Gnomad4 NFE AF: 0.00174

Gnomad4 OTH AF: 0.000976

Alfa AF: 0.00213 Hom.: 0

Bravo AF: 0.00118

ExAC AF: 0.0000691 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 10, 2022	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 22, 2016

- -

Intellectual disability-epilepsy-extrapyramidal syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Uncertain significance, criteria provided, single submitter

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Sep 07, 2023

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2022

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	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.76
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	0.31	N
REVEL	Benign	0.076
Sift	Benign	0.50	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.43
MPC		0.73
ClinPred		0.021	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.062
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs767318857; hg19: chr11-694992; COSMIC: COSV58608371; COSMIC: COSV58608371;