12-122867267-G-A

Variant names:

• chr12-122867267-G-A
• rs756622487
• NM_024667.3:c.707C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024667.3(VPS37B):​c.707C>T​(p.Pro236Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000704 in 1,420,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. P236Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: VPS37B NM_024667.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.62
• 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]

ENSG00000256152 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24635848).

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.707C>T	p.Pro236Leu	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.707C>T	p.Pro236Leu	missense	Exon 4 of 4	ENSP00000267202.2	Q9H9H4
	VPS37B	ENST00000535765.5	TSL:3	c.701C>T	p.Pro234Leu	missense	Exon 4 of 4	ENSP00000446075.1	F5H4M0
	VPS37B	ENST00000852158.1		c.452C>T	p.Pro151Leu	missense	Exon 2 of 2	ENSP00000522217.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1420476 Hom.: 0 Cov.: 33 AF XY: 0.00000142 AC XY: 1 AN XY: 703746

African (AFR) AF: 0.00 AC: 0 AN: 32256

American (AMR) AF: 0.00 AC: 0 AN: 38536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22828

East Asian (EAS) AF: 0.00 AC: 0 AN: 39510

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5212

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094078

Other (OTH) AF: 0.00 AC: 0 AN: 58652

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.016
Eigen_PC	Benign	-0.0086
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	2.0	M
PhyloP100		5.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.19
Sift	Benign	0.056	T
Sift4G	Uncertain	0.0030	D
Polyphen		0.36	B
Vest4		0.14
MutPred		0.26		Loss of glycosylation at P236 (P = 0.0711)
MVP		0.23
MPC		0.27
ClinPred		0.85	D
GERP RS		5.2
Varity_R		0.10
gMVP		0.27
Mutation Taster		=85/15	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: rs756622487; hg19: chr12-123351814;