11-694797-G-T

Variant names:

• chr11-694797-G-T
• rs763981738
• NM_021008.4:c.251C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021008.4(DEAF1):​c.251C>A​(p.Pro84His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000804 in 1,243,508 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P84R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: DEAF1 NM_021008.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.18
• 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: 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.251C>A	p.Pro84His	missense	Exon 1 of 12	NP_066288.2
	DEAF1	NM_001440883.1		c.251C>A	p.Pro84His	missense	Exon 1 of 11	NP_001427812.1
	DEAF1	NM_001440884.1		c.251C>A	p.Pro84His	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.251C>A	p.Pro84His	missense	Exon 1 of 12	ENSP00000371846.3	O75398-1
	DEAF1	ENST00000882097.1		c.251C>A	p.Pro84His	missense	Exon 1 of 13	ENSP00000552156.1
	DEAF1	ENST00000685854.1		c.47C>A	p.Pro16His	missense	Exon 1 of 14	ENSP00000508801.1	A0A8I5KQY1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.04e-7 AC: 1 AN: 1243508 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 609140

African (AFR) AF: 0.0000395 AC: 1 AN: 25328

American (AMR) AF: 0.00 AC: 0 AN: 19574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19764

East Asian (EAS) AF: 0.00 AC: 0 AN: 27080

South Asian (SAS) AF: 0.00 AC: 0 AN: 58620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3610

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1007972

Other (OTH) AF: 0.00 AC: 0 AN: 51016

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.2
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.14
MutPred		0.25		Gain of helix (P = 0.0225)
MVP		0.81
MPC		1.4
ClinPred		0.89	D
GERP RS		2.6
PromoterAI		-0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.51
Mutation Taster		=88/12	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: rs763981738; hg19: chr11-694797;