11-694795-C-A

Variant names:

• chr11-694795-C-A
• rs1708369497
• NM_021008.4:c.253G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001440885.1(DEAF1):​c.-344G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000816 in 1,225,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: DEAF1 NM_001440885.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.338
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27014983).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440885.1. 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.253G>T	p.Gly85Cys	missense	Exon 1 of 12	NP_066288.2
	DEAF1	NM_001440885.1		c.-344G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_001427814.1
	DEAF1	NM_001440886.1		c.-1744G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_001427815.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEAF1	ENST00000382409.4	TSL:1 MANE Select	c.253G>T	p.Gly85Cys	missense	Exon 1 of 12	ENSP00000371846.3	O75398-1
	DEAF1	ENST00000882097.1		c.253G>T	p.Gly85Cys	missense	Exon 1 of 13	ENSP00000552156.1
	DEAF1	ENST00000685854.1		c.49G>T	p.Gly17Cys	missense	Exon 1 of 14	ENSP00000508801.1	A0A8I5KQY1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.16e-7 AC: 1 AN: 1225442 Hom.: 0 Cov.: 32 AF XY: 0.00000167 AC XY: 1 AN XY: 598834

African (AFR) AF: 0.00 AC: 0 AN: 24730

American (AMR) AF: 0.00 AC: 0 AN: 15998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18810

East Asian (EAS) AF: 0.00 AC: 0 AN: 26918

South Asian (SAS) AF: 0.0000181 AC: 1 AN: 55170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3520

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1000146

Other (OTH) AF: 0.00 AC: 0 AN: 50218

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.34
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.11
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.092	T
Polyphen		0.78	P
Vest4		0.16
MutPred		0.17		Gain of catalytic residue at P84 (P = 0.0074)
MVP		0.58
MPC		1.5
ClinPred		0.48	T
GERP RS		1.7
PromoterAI		0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.23
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1708369497; hg19: chr11-694795;