11-694968-G-C

Variant names:

• chr11-694968-G-C
• rs1400909690
• NM_021008.4:c.80C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_021008.4(DEAF1):​c.80C>G​(p.Ala27Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A27V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DEAF1 NM_021008.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.759
• Publications: 0 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: 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20514435).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEAF1	NM_021008.4	MANE Select	c.80C>G	p.Ala27Gly	missense	Exon 1 of 12	NP_066288.2
	DEAF1	NM_001440883.1		c.80C>G	p.Ala27Gly	missense	Exon 1 of 11	NP_001427812.1
	DEAF1	NM_001440884.1		c.80C>G	p.Ala27Gly	missense	Exon 1 of 11	NP_001427813.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEAF1	ENST00000382409.4	TSL:1 MANE Select	c.80C>G	p.Ala27Gly	missense	Exon 1 of 12	ENSP00000371846.3
	DEAF1	ENST00000882097.1		c.80C>G	p.Ala27Gly	missense	Exon 1 of 13	ENSP00000552156.1
	DEAF1	ENST00000917805.1		c.80C>G	p.Ala27Gly	missense	Exon 1 of 12	ENSP00000587864.1

Frequencies

GnomAD3 genomes AF: 0.00000689 AC: 1 AN: 145146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000245

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000174 AC: 16 AN: 919926 Hom.: 0 Cov.: 32 AF XY: 0.0000227 AC XY: 10 AN XY: 440526

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000579 AC: 1 AN: 17286

American (AMR) AF: 0.00 AC: 0 AN: 4308

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 1 AN: 9692

East Asian (EAS) AF: 0.000165 AC: 2 AN: 12144

South Asian (SAS) AF: 0.00 AC: 0 AN: 25078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2144

European-Non Finnish (NFE) AF: 0.0000124 AC: 10 AN: 809156

Other (OTH) AF: 0.0000617 AC: 2 AN: 32418

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 145276 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 70842

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40212

American (AMR) AF: 0.00 AC: 0 AN: 14598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3330

East Asian (EAS) AF: 0.00 AC: 0 AN: 4460

South Asian (SAS) AF: 0.00 AC: 0 AN: 4096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65908

Other (OTH) AF: 0.00 AC: 0 AN: 2030

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.76
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.053
Sift	Benign	0.11	T
Sift4G	Uncertain	0.032	D
Polyphen		0.42	B
Vest4		0.17
MutPred		0.35		Loss of stability (P = 0.1239)
MVP		0.57
MPC		1.6
ClinPred		0.56	D
GERP RS		2.4
PromoterAI		-0.13	Neutral
Varity_R		0.083
gMVP		0.27
Mutation Taster		=74/26	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: rs1400909690; hg19: chr11-694968;