7-73668040-C-T

Variant names:

• chr7-73668040-C-T
• rs1797421370
• NM_001077621.2:c.82C>T

Variant summary

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

The NM_001077621.2(VPS37D):​c.82C>T​(p.Arg28Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VPS37D NM_001077621.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80

Genes affected

VPS37D (HGNC:18287): (VPS37D subunit of ESCRT-I) Predicted to be involved in protein targeting to membrane; protein targeting to vacuole; and ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway. Located in extracellular exosome. Part of ESCRT I complex. [provided by Alliance of Genome Resources, Apr 2022]

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 rank	MANE	Protein	UniProt
VPS37D	NM_001077621.2	c.82C>T	p.Arg28Trp	missense_variant	Exon 1 of 4	ENST00000324941.5	NP_001071089.1
VPS37D	XM_017011779.2	c.16-1379C>T		intron_variant	Intron 1 of 3		XP_016867268.1
VPS37D	XM_047419927.1	c.-416C>T		upstream_gene_variant			XP_047275883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS37D	ENST00000324941.5	c.82C>T	p.Arg28Trp	missense_variant	Exon 1 of 4	1	NM_001077621.2	ENSP00000320416.4
VPS37D	ENST00000451519.1	c.82C>T	p.Arg28Trp	missense_variant	Exon 1 of 2	5		ENSP00000413337.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1017116 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 488090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.82C>T (p.R28W) alteration is located in exon 1 (coding exon 1) of the VPS37D gene. This alteration results from a C to T substitution at nucleotide position 82, causing the arginine (R) at amino acid position 28 to be replaced by a tryptophan (W). 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	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.028
Eigen_PC	Benign	-0.055
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.76	T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.0	D;N
REVEL	Benign	0.20
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.97	D;.
Vest4		0.40
MutPred		0.55		Loss of disorder (P = 0);Loss of disorder (P = 0);
MVP		0.082
MPC		3.4
ClinPred		0.92	D
GERP RS		1.8
Varity_R		0.19
gMVP		0.43

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: rs1797421370; hg19: chr7-73082370;