rs34114147

chr11-644614-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021008.4(DEAF1):c.1634C>G(p.Ala545Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00821 in 1,612,816 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (71 hom.)
• Consequence: DEAF1 NM_021008.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.14

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045463145).
• BP6: Variant 11-644614-G-C is Benign according to our data. Variant chr11-644614-G-C is described in ClinVar as [Benign]. Clinvar id is 434924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-644614-G-C is described in Lovd as [Benign]. Variant chr11-644614-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00672 (1024/152278) while in subpopulation AMR AF= 0.0127 (195/15304). AF 95% confidence interval is 0.0113. There are 13 homozygotes in gnomad4. There are 483 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEAF1	NM_021008.4	c.1634C>G	p.Ala545Gly	missense_variant	12/12	ENST00000382409.4
DEAF1	NM_001293634.1	c.1409C>G	p.Ala470Gly	missense_variant	11/11
DEAF1	NM_001367390.1	c.908C>G	p.Ala303Gly	missense_variant	12/12
DEAF1	XM_047426251.1	c.908C>G	p.Ala303Gly	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEAF1	ENST00000382409.4	c.1634C>G	p.Ala545Gly	missense_variant	12/12	1	NM_021008.4	P1

Frequencies

GnomAD3 genomes AF: 0.00674 AC: 1025 AN: 152160 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00941

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00662 AC: 1650 AN: 249184 Hom.: 11 AF XY: 0.00627 AC XY: 847 AN XY: 135102

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.0113

Gnomad ASJ exome AF: 0.00459

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00559

Gnomad NFE exome AF: 0.00889

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.00836 AC: 12212 AN: 1460538 Hom.: 71 Cov.: 31 AF XY: 0.00798 AC XY: 5799 AN XY: 726594

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.0113

Gnomad4 ASJ exome AF: 0.00513

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00627

Gnomad4 NFE exome AF: 0.00966

Gnomad4 OTH exome AF: 0.00747

GnomAD4 genome AF: 0.00672 AC: 1024 AN: 152278 Hom.: 13 Cov.: 32 AF XY: 0.00649 AC XY: 483 AN XY: 74464

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00574

Gnomad4 NFE AF: 0.00941

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00751 Hom.: 4

Bravo AF: 0.00744

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00965 AC: 83

ExAC AF: 0.00597 AC: 725

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DEAF1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 23, 2018	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 14, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.13
Sift	Benign	0.19	T
Sift4G	Benign	0.55	T
Polyphen		0.0010	B
Vest4		0.053
MVP		0.77
MPC		0.68
ClinPred		0.0028	T
GERP RS		3.3
Varity_R		0.047
gMVP		0.14

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: rs34114147; hg19: chr11-644614; COSMIC: COSV99448606; COSMIC: COSV99448606;