5-60603416-C-T

Variant names:

• chr5-60603416-C-T
• rs754576713
• NM_018369.3:c.1217G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018369.3(DEPDC1B):​c.1217G>A​(p.Arg406His) variant causes a missense change. The variant allele was found at a frequency of 0.0000383 in 1,591,004 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: DEPDC1B NM_018369.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40

Genes affected

DEPDC1B (HGNC:24902): (DEP domain containing 1B) Predicted to enable GTPase activator activity. Involved in cell migration and positive regulation of Wnt signaling pathway. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08329928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC1B	NM_018369.3	c.1217G>A	p.Arg406His	missense_variant	Exon 9 of 11	ENST00000265036.10	NP_060839.2
DEPDC1B	NM_001145208.2	c.1217G>A	p.Arg406His	missense_variant	Exon 9 of 10		NP_001138680.1
DEPDC1B	XM_011543509.3	c.1172G>A	p.Arg391His	missense_variant	Exon 9 of 11		XP_011541811.1
DEPDC1B	XM_047417369.1	c.1172G>A	p.Arg391His	missense_variant	Exon 9 of 10		XP_047273325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC1B	ENST00000265036.10	c.1217G>A	p.Arg406His	missense_variant	Exon 9 of 11	1	NM_018369.3	ENSP00000265036.5
DEPDC1B	ENST00000453022.6	c.1217G>A	p.Arg406His	missense_variant	Exon 9 of 10	2		ENSP00000389101.2
DEPDC1B	ENST00000512078.5	n.*1214G>A		non_coding_transcript_exon_variant	Exon 10 of 11	2		ENSP00000427527.1
DEPDC1B	ENST00000512078.5	n.*1214G>A		3_prime_UTR_variant	Exon 10 of 11	2		ENSP00000427527.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000130 AC: 3 AN: 229978 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 124768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000708

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000379

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000410 AC: 59 AN: 1438868 Hom.: 0 Cov.: 29 AF XY: 0.0000280 AC XY: 20 AN XY: 715540

Gnomad4 AFR exome AF: 0.0000312

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000612

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000371

Gnomad4 OTH exome AF: 0.0000506

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74316

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1217G>A (p.R406H) alteration is located in exon 9 (coding exon 9) of the DEPDC1B gene. This alteration results from a G to A substitution at nucleotide position 1217, causing the arginine (R) at amino acid position 406 to be replaced by a histidine (H). 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	0.081
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.54
DEOGEN2	Benign	0.034	T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.083	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-1.2	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	2.5	N;N
REVEL	Benign	0.17
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0030	B;.
Vest4		0.22
MutPred		0.38		Loss of catalytic residue at R406 (P = 0.0494);Loss of catalytic residue at R406 (P = 0.0494);
MVP		0.77
MPC		0.21
ClinPred		0.14	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.28

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: rs754576713; hg19: chr5-59899243; COSMIC: COSV54008375; COSMIC: COSV54008375;