12-122867351-G-C

Variant names:

• chr12-122867351-G-C
• rs761157980
• NM_024667.3:c.623C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024667.3(VPS37B):​c.623C>G​(p.Pro208Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. P208H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: VPS37B NM_024667.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.20
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024667.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS37B	NM_024667.3	MANE Select	c.623C>G	p.Pro208Arg	missense	Exon 4 of 4	NP_078943.1	Q9H9H4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS37B	ENST00000267202.7	TSL:1 MANE Select	c.623C>G	p.Pro208Arg	missense	Exon 4 of 4	ENSP00000267202.2	Q9H9H4
	VPS37B	ENST00000535765.5	TSL:3	c.617C>G	p.Pro206Arg	missense	Exon 4 of 4	ENSP00000446075.1	F5H4M0
	VPS37B	ENST00000852158.1		c.368C>G	p.Pro123Arg	missense	Exon 2 of 2	ENSP00000522217.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.28
Sift	Benign	0.18	T
Sift4G	Uncertain	0.024	D
Polyphen		0.96	D
Vest4		0.49
MutPred		0.38		Loss of glycosylation at P208 (P = 0.0112)
MVP		0.37
MPC		0.73
ClinPred		0.97	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.55
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs761157980; hg19: chr12-123351898;