12-122867357-C-A

Variant names:

• chr12-122867357-C-A
• rs201917286
• NM_024667.3:c.617G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024667.3(VPS37B):​c.617G>T​(p.Arg206Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R206H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VPS37B NM_024667.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.24

Genes affected

VPS37B (HGNC:25754): (VPS37B subunit of ESCRT-I) Enables calcium-dependent protein binding activity. Involved in positive regulation of viral budding via host ESCRT complex. Located in endosome membrane; midbody; and plasma membrane. Part of ESCRT I complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32567465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS37B	NM_024667.3	c.617G>T	p.Arg206Leu	missense_variant	Exon 4 of 4	ENST00000267202.7	NP_078943.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS37B	ENST00000267202.7	c.617G>T	p.Arg206Leu	missense_variant	Exon 4 of 4	1	NM_024667.3	ENSP00000267202.2
VPS37B	ENST00000535765.5	c.611G>T	p.Arg204Leu	missense_variant	Exon 4 of 4	3		ENSP00000446075.1
VPS37B	ENST00000371248.3	c.*58G>T		downstream_gene_variant		3		ENSP00000360294.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448958 Hom.: 0 Cov.: 43 AF XY: 0.00 AC XY: 0 AN XY: 720168

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.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.27
Sift	Benign	0.81	T;T
Sift4G	Benign	0.27	T;.
Polyphen		0.99	D;.
Vest4		0.48
MutPred		0.22		Loss of methylation at R206 (P = 0.0188);.;
MVP		0.26
MPC		0.91
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.49

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: rs201917286; hg19: chr12-123351904;