chr11-61132019-C-G

Position:

• chr11-61132019-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017966.5(VPS37C):​c.869G>C​(p.Arg290Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VPS37C NM_017966.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.33

Genes affected

VPS37C (HGNC:26097): (VPS37C subunit of ESCRT-I) VPS37C is a subunit of ESCRT-I (endosomal sorting complex required for transport I), a complex in the class E vacuolar protein sorting (VPS) pathway required for sorting ubiquitinated transmembrane proteins into internal vesicles of multivesicular bodies (Eastman et al., 2005 [PubMed 15509564]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061584085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS37C	NM_017966.5	c.869G>C	p.Arg290Thr	missense_variant	5/5	ENST00000301765.10	NP_060436.4
VPS37C	XM_005274077.4	c.869G>C	p.Arg290Thr	missense_variant	5/5		XP_005274134.1
VPS37C	XM_047427178.1	c.*510G>C		3_prime_UTR_variant	5/5		XP_047283134.1
VPS37C	XM_047427179.1	c.*510G>C		3_prime_UTR_variant	5/5		XP_047283135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS37C	ENST00000301765.10	c.869G>C	p.Arg290Thr	missense_variant	5/5	1	NM_017966.5	ENSP00000301765.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 53

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 2024

The c.869G>C (p.R290T) alteration is located in exon 5 (coding exon 4) of the VPS37C gene. This alteration results from a G to C substitution at nucleotide position 869, causing the arginine (R) at amino acid position 290 to be replaced by a threonine (T). 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	0.090
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.14
DANN	Benign	0.45
DEOGEN2	Benign	0.010	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.0020
Sift	Uncertain	0.028	D
Sift4G	Benign	0.48	T
Polyphen		0.039	B
Vest4		0.17
MutPred		0.27		Gain of phosphorylation at R290 (P = 0.0069);
MVP		0.092
MPC		0.14
ClinPred		0.031	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.032
gMVP		0.37

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: rs1861272792; hg19: chr11-60899491;