chr11-694965-GCCGCCGCCACAGCGGCCGCGGCCGCCA-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4BP6BS2

The NM_021008.4(DEAF1):c.56_82delTGGCGGCCGCGGCCGCTGTGGCGGCGG(p.Val19_Ala27del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,140,816 control chromosomes in the GnomAD database, including 23 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V19V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 23 hom. )

Consequence

DEAF1
NM_021008.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 2.45

Publications

0 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: Likely_benign. The variant received -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_021008.4.

BP6

Variant 11-694965-GCCGCCGCCACAGCGGCCGCGGCCGCCA-G is Benign according to our data. Variant chr11-694965-GCCGCCGCCACAGCGGCCGCGGCCGCCA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434934.

BS2

High Homozygotes in GnomAdExome4 at 23 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEAF1	NM_021008.4 link	c.56_82delTGGCGGCCGCGGCCGCTGTGGCGGCGG	p.Val19_Ala27del	disruptive_inframe_deletion	Exon 1 of 12	ENST00000382409.4	NP_066288.2	O75398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEAF1	ENST00000382409.4 link	c.56_82delTGGCGGCCGCGGCCGCTGTGGCGGCGG	p.Val19_Ala27del	disruptive_inframe_deletion	Exon 1 of 12	1	NM_021008.4	ENSP00000371846.3		O75398-1

Frequencies

GnomAD3 genomes

AF:

0.000190

AC:

AN:

147146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000148

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000203

Gnomad ASJ

AF:

0.000300

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000677

Gnomad FIN

AF:

0.000103

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000211

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000371

AC:

AN:

29622

AF XY:

0.000362

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000513

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000209

AC:

208

AN:

993560

Hom.:

AF XY:

0.000220

AC XY:

105

AN XY:

477822

show subpopulations

African (AFR)

AF:

0.000158

AC:

AN:

18992

American (AMR)

AF:

0.000328

AC:

AN:

6106

Ashkenazi Jewish (ASJ)

AF:

0.0000861

AC:

AN:

11616

East Asian (EAS)

AF:

0.000316

AC:

AN:

15828

South Asian (SAS)

AF:

0.000785

AC:

AN:

26768

European-Finnish (FIN)

AF:

0.000174

AC:

AN:

11520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2440

European-Non Finnish (NFE)

AF:

0.000193

AC:

167

AN:

864068

Other (OTH)

AF:

0.000193

AC:

AN:

36222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.620

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000190

AC:

AN:

147256

Hom.:

Cov.:

AF XY:

0.000251

AC XY:

AN XY:

71830

show subpopulations

African (AFR)

AF:

0.000147

AC:

AN:

40712

American (AMR)

AF:

0.000203

AC:

AN:

14792

Ashkenazi Jewish (ASJ)

AF:

0.000300

AC:

AN:

3336

East Asian (EAS)

AF:

0.00

AC:

AN:

4784

South Asian (SAS)

AF:

0.000676

AC:

AN:

4438

European-Finnish (FIN)

AF:

0.000103

AC:

AN:

9688

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000211

AC:

AN:

66286

Other (OTH)

AF:

0.00

AC:

AN:

2034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

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:

0.0000712

Hom.:

Bravo

AF:

0.000155

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.56_82del, results in the deletion of 9 amino acid(s) of the DEAF1 protein (p.Val19_Ala27del), but otherwise preserves the integrity of the reading frame. 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: 434934). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DEAF1: BP3 -

not specified

Uncertain:1

Sep 30, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Mutation Taster

=197/3

polymorphism

(source)

Splicing

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