rs117691319

Positions:

• chr11-686888-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_021008.4(DEAF1):​c.774C>T​(p.Tyr258=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,614,214 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 33)
  • Exomes 𝑓: 0.012 (111 hom.)
• Consequence: DEAF1 NM_021008.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.352

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 11-686888-G-A is Benign according to our data. Variant chr11-686888-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 447242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.352 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00997 (1519/152346) while in subpopulation NFE AF= 0.0141 (959/68032). AF 95% confidence interval is 0.0134. There are 12 homozygotes in gnomad4. There are 782 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEAF1	NM_021008.4	c.774C>T	p.Tyr258=	synonymous_variant	5/12	ENST00000382409.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEAF1	ENST00000382409.4	c.774C>T	p.Tyr258=	synonymous_variant	5/12	1	NM_021008.4	P1

Frequencies

GnomAD3 genomes AF: 0.00998 AC: 1519 AN: 152230 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00680

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0249

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0103 AC: 2594 AN: 251178 Hom.: 29 AF XY: 0.0104 AC XY: 1418 AN XY: 135812

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00544

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.0251

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.00946

GnomAD4 exome AF: 0.0119 AC: 17416 AN: 1461868 Hom.: 111 Cov.: 33 AF XY: 0.0117 AC XY: 8521 AN XY: 727232

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.00530

Gnomad4 ASJ exome AF: 0.0145

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00205

Gnomad4 FIN exome AF: 0.0265

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.00950

GnomAD4 genome AF: 0.00997 AC: 1519 AN: 152346 Hom.: 12 Cov.: 33 AF XY: 0.0105 AC XY: 782 AN XY: 74502

Gnomad4 AFR AF: 0.00226

Gnomad4 AMR AF: 0.00679

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0249

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.0120 Hom.: 9

Bravo AF: 0.00833

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0152

EpiControl AF: 0.0138

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	DEAF1: BP4, BP7, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 07, 2017

- -

Intellectual disability, autosomal dominant 24;C4310683:Intellectual disability-epilepsy-extrapyramidal syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 21, 2022

- -

DEAF1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	1.1
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs117691319; hg19: chr11-686888; COSMIC: COSV100102512; COSMIC: COSV100102512;