rs10902188

Variant names:

• chr11-654043-G-A
• rs10902188
• NM_021008.4:c.1512C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021008.4(DEAF1):​c.1512C>T​(p.Cys504Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0888 in 1,612,784 control chromosomes in the GnomAD database, including 7,246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (670 hom., cov: 30)
  • Exomes 𝑓: 0.089 (6576 hom.)
• Consequence: DEAF1 NM_021008.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.625
• Publications: 23 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]

DEAF1 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 24

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• intellectual disability-epilepsy-extrapyramidal syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: SD Classification: STRONG Submitted by: Illumina
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 11-654043-G-A is Benign according to our data. Variant chr11-654043-G-A is described in ClinVar as Benign. ClinVar VariationId is 585773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.625 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

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.1512C>T	p.Cys504Cys	synonymous	Exon 11 of 12	NP_066288.2
	DEAF1	NM_001440884.1		c.1383C>T	p.Cys461Cys	synonymous	Exon 10 of 11	NP_001427813.1
	DEAF1	NM_001293634.2		c.1287C>T	p.Cys429Cys	synonymous	Exon 10 of 11	NP_001280563.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEAF1	ENST00000382409.4	TSL:1 MANE Select	c.1512C>T	p.Cys504Cys	synonymous	Exon 11 of 12	ENSP00000371846.3
	DEAF1	ENST00000527170.5	TSL:1	n.873C>T		non_coding_transcript_exon	Exon 8 of 10	ENSP00000431563.1
	DEAF1	ENST00000685854.1		c.1308C>T	p.Cys436Cys	synonymous	Exon 11 of 14	ENSP00000508801.1

Frequencies

GnomAD3 genomes AF: 0.0858 AC: 13036 AN: 151894 Hom.: 665 Cov.: 30

Gnomad AFR AF: 0.0549

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.0724

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.0833

Gnomad FIN AF: 0.0488

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0849

Gnomad OTH AF: 0.0750

GnomAD2 exomes AF: 0.103 AC: 25780 AN: 249718 AF XY: 0.0975

Gnomad AFR exome AF: 0.0541

Gnomad AMR exome AF: 0.221

Gnomad ASJ exome AF: 0.0798

Gnomad EAS exome AF: 0.157

Gnomad FIN exome AF: 0.0527

Gnomad NFE exome AF: 0.0837

Gnomad OTH exome AF: 0.0920

GnomAD4 exome AF: 0.0891 AC: 130118 AN: 1460776 Hom.: 6576 Cov.: 34 AF XY: 0.0883 AC XY: 64180 AN XY: 726688

African (AFR) AF: 0.0545 AC: 1822 AN: 33456

American (AMR) AF: 0.216 AC: 9666 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0796 AC: 2080 AN: 26134

East Asian (EAS) AF: 0.158 AC: 6260 AN: 39686

South Asian (SAS) AF: 0.0774 AC: 6671 AN: 86236

European-Finnish (FIN) AF: 0.0519 AC: 2749 AN: 52928

Middle Eastern (MID) AF: 0.0885 AC: 508 AN: 5740

European-Non Finnish (NFE) AF: 0.0855 AC: 95077 AN: 1111550

Other (OTH) AF: 0.0875 AC: 5285 AN: 60370

GnomAD4 genome AF: 0.0859 AC: 13059 AN: 152008 Hom.: 670 Cov.: 30 AF XY: 0.0879 AC XY: 6528 AN XY: 74300

African (AFR) AF: 0.0550 AC: 2280 AN: 41474

American (AMR) AF: 0.183 AC: 2793 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0724 AC: 251 AN: 3466

East Asian (EAS) AF: 0.154 AC: 792 AN: 5154

South Asian (SAS) AF: 0.0834 AC: 402 AN: 4822

European-Finnish (FIN) AF: 0.0488 AC: 516 AN: 10568

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0849 AC: 5771 AN: 67952

Other (OTH) AF: 0.0794 AC: 168 AN: 2116

Alfa AF: 0.0863 Hom.: 1242

Bravo AF: 0.0939

Asia WGS AF: 0.148 AC: 514 AN: 3478

EpiCase AF: 0.0832

EpiControl AF: 0.0883

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.83
DANN	Benign	0.71
PhyloP100		-0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10902188; hg19: chr11-654043; COSMIC: COSV58607050;