11-694992-A-G

Variant names:

• chr11-694992-A-G
• rs767318857
• NM_021008.4:c.56T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 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. 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 0.125
• Publications: 1 publications found

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]

EPS8L2 Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive 106

  Inheritance: AR Classification: STRONG Submitted by: 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

ACMG classification

Our verdict: Benign. The variant received -12 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.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021008.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEAF1	NM_021008.4	MANE Select	c.56T>C	p.Val19Ala	missense	Exon 1 of 12	NP_066288.2
	DEAF1	NM_001440883.1		c.56T>C	p.Val19Ala	missense	Exon 1 of 11	NP_001427812.1
	DEAF1	NM_001440884.1		c.56T>C	p.Val19Ala	missense	Exon 1 of 11	NP_001427813.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEAF1	ENST00000382409.4	TSL:1 MANE Select	c.56T>C	p.Val19Ala	missense	Exon 1 of 12	ENSP00000371846.3	O75398-1
	DEAF1	ENST00000882097.1		c.56T>C	p.Val19Ala	missense	Exon 1 of 13	ENSP00000552156.1
	DEAF1	ENST00000917805.1		c.56T>C	p.Val19Ala	missense	Exon 1 of 12	ENSP00000587864.1

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

GnomAD2 exomes AF: 0.000972 AC: 28 AN: 28818 AF XY: 0.000861

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

African (AFR) AF: 0.00111 AC: 19 AN: 17124

American (AMR) AF: 0.00119 AC: 6 AN: 5062

Ashkenazi Jewish (ASJ) AF: 0.000609 AC: 6 AN: 9852

East Asian (EAS) AF: 0.00124 AC: 14 AN: 11248

South Asian (SAS) AF: 0.000664 AC: 17 AN: 25598

European-Finnish (FIN) AF: 0.00213 AC: 15 AN: 7052

Middle Eastern (MID) AF: 0.000479 AC: 1 AN: 2088

European-Non Finnish (NFE) AF: 0.00205 AC: 1649 AN: 806308

Other (OTH) AF: 0.00131 AC: 42 AN: 32050

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

African (AFR) AF: 0.000825 AC: 33 AN: 39978

American (AMR) AF: 0.000894 AC: 13 AN: 14538

Ashkenazi Jewish (ASJ) AF: 0.000293 AC: 1 AN: 3410

East Asian (EAS) AF: 0.00190 AC: 8 AN: 4216

South Asian (SAS) AF: 0.000256 AC: 1 AN: 3904

European-Finnish (FIN) AF: 0.000428 AC: 4 AN: 9350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00174 AC: 115 AN: 66000

Other (OTH) AF: 0.000976 AC: 2 AN: 2050

Alfa AF: 0.00213 Hom.: 0

Bravo AF: 0.00118

ExAC AF: 0.0000691 AC: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	-	1	DEAF1-related disorder (1)
-	1	-	Intellectual disability-epilepsy-extrapyramidal syndrome (1)
-	1	-	Intellectual disability, autosomal dominant 24 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.13
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
PromoterAI		0.0070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.062
gMVP		0.22
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

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