11-644554-A-ACGGT

Position:

• chr11-644554-A-ACGGT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_021008.4(DEAF1):​c.1690_1693dupACCG​(p.Val565fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DEAF1 NM_021008.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.99

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00294 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEAF1	NM_021008.4	c.1690_1693dupACCG	p.Val565fs	frameshift_variant	12/12	ENST00000382409.4	NP_066288.2
DEAF1	NM_001293634.1	c.1465_1468dupACCG	p.Val490fs	frameshift_variant	11/11		NP_001280563.1
DEAF1	NM_001367390.1	c.964_967dupACCG	p.Val323fs	frameshift_variant	12/12		NP_001354319.1
DEAF1	XM_047426251.1	c.964_967dupACCG	p.Val323fs	frameshift_variant	12/12		XP_047282207.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEAF1	ENST00000382409.4	c.1690_1693dupACCG	p.Val565fs	frameshift_variant	12/12	1	NM_021008.4	ENSP00000371846.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 24 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The observed frameshift c.1690_1693dup p.Val565AspfsTer19 variant in DEAF1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Val565AspfsTer19 variant is absent in gnomAD Exomes. This variant has not been submitted to the ClinVar database. This variant causes a frameshift starting with codon Valine 565, changes this amino acid to Aspartic Acid residue, and creates a premature Stop codon at position 19 of the new reading frame, denoted p.Val565AspfsTer19. However, since this variant is present in the last exon, functional studies will be required to prove protein truncation to prove protein truncation. As loss of function is not a known mechanism of this gene, this variant is classified as Variant of uncertain significance VUS. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-644554;