12-100263637-C-A

Position:

• chr12-100263637-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000550587.6(DEPDC4):​c.414G>T​(p.Met138Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DEPDC4 ENST00000550587.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.28

Genes affected

DEPDC4 (HGNC:22952): (DEP domain containing 4) Predicted to be involved in intracellular signal transduction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039333552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEPDC4	NM_001364818.2	c.414G>T	p.Met138Ile	missense_variant	2/10	ENST00000550587.6	NP_001351747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEPDC4	ENST00000550587.6	c.414G>T	p.Met138Ile	missense_variant	2/10	1	NM_001364818.2	ENSP00000448385	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.414G>T (p.M138I) alteration is located in exon 2 (coding exon 2) of the DEPDC4 gene. This alteration results from a G to T substitution at nucleotide position 414, causing the methionine (M) at amino acid position 138 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.1
DANN	Benign	0.67
DEOGEN2	Benign	0.014	T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.50	T;T;T;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.039	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.26	N;.;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.58	N;N;N;N
REVEL	Benign	0.015
Sift	Benign	0.30	T;T;T;T
Sift4G	Benign	0.36	T;.;.;T
Polyphen		0.0020	B;B;B;.
Vest4		0.031
MutPred		0.44		Gain of methylation at K139 (P = 0.0198);Gain of methylation at K139 (P = 0.0198);.;.;
MVP		0.12
MPC		0.042
ClinPred		0.18	T
GERP RS		1.6
Varity_R		0.11
gMVP		0.076

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-100657415;