11-674094-G-C

Variant names:

• chr11-674094-G-C
• rs4073591
• NM_021008.4:c.1503+442C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021008.4(DEAF1):​c.1503+442C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000914 in 109,386 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: 31)
  • Exomes 𝑓: 0.0000091 (0 hom.)
• Consequence: DEAF1 NM_021008.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• Publications: 7 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

ENSG00000255158 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEAF1	NM_021008.4	c.1503+442C>G		intron_variant	Intron 10 of 11	ENST00000382409.4	NP_066288.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEAF1	ENST00000382409.4	c.1503+442C>G		intron_variant	Intron 10 of 11	1	NM_021008.4	ENSP00000371846.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000914 AC: 1 AN: 109386 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 58366

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 3472

American (AMR) AF: 0.00 AC: 0 AN: 4978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2600

East Asian (EAS) AF: 0.00 AC: 0 AN: 4830

South Asian (SAS) AF: 0.00 AC: 0 AN: 18560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 362

European-Non Finnish (NFE) AF: 0.0000156 AC: 1 AN: 64194

Other (OTH) AF: 0.00 AC: 0 AN: 5456

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.4
DANN	Benign	0.51
PhyloP100		1.3

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: rs4073591; hg19: chr11-674094;