chr11-694797-G-C

Position:

• chr11-694797-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021008.4(DEAF1):​c.251C>G​(p.Pro84Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000038 in 1,395,126 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P84P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: DEAF1 NM_021008.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.18

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]

EPS8L2 (HGNC:21296): (EPS8 signaling adaptor L2) This gene encodes a member of the EPS8 gene family. The encoded protein, like other members of the family, is thought to link growth factor stimulation to actin organization, generating functional redundancy in the pathways that regulate actin cytoskeletal remodeling. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEAF1	NM_021008.4	c.251C>G	p.Pro84Arg	missense_variant	1/12	ENST00000382409.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEAF1	ENST00000382409.4	c.251C>G	p.Pro84Arg	missense_variant	1/12	1	NM_021008.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000528 AC: 8 AN: 151512 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000740

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.0000197 AC: 1 AN: 50800 Hom.: 0 AF XY: 0.0000335 AC XY: 1 AN XY: 29812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000543

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000362 AC: 45 AN: 1243508 Hom.: 0 Cov.: 32 AF XY: 0.0000345 AC XY: 21 AN XY: 609140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000153

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000367

Gnomad4 OTH exome AF: 0.0000392

GnomAD4 genome AF: 0.0000528 AC: 8 AN: 151618 Hom.: 0 Cov.: 32 AF XY: 0.0000675 AC XY: 5 AN XY: 74038

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000740

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000233 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 84 of the DEAF1 protein (p.Pro84Arg). This variant is present in population databases (rs763981738, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DEAF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2053731). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DEAF1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.036	D
Polyphen		1.0	D
Vest4		0.13
MutPred		0.30		Gain of helix (P = 0.0117);
MVP		0.81
MPC		0.96
ClinPred		0.37	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.57

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: rs763981738; hg19: chr11-694797;