11-61132493-A-G

Position:

• chr11-61132493-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_017966.5(VPS37C):​c.395T>C​(p.Phe132Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS37C NM_017966.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.70

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS37C	NM_017966.5	c.395T>C	p.Phe132Ser	missense_variant	5/5	ENST00000301765.10	NP_060436.4
VPS37C	XM_005274077.4	c.395T>C	p.Phe132Ser	missense_variant	5/5		XP_005274134.1
VPS37C	XM_047427178.1	c.*36T>C		3_prime_UTR_variant	5/5		XP_047283134.1
VPS37C	XM_047427179.1	c.*36T>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.395T>C	p.Phe132Ser	missense_variant	5/5	1	NM_017966.5	ENSP00000301765.5
VPS37C	ENST00000538036.1	c.395T>C	p.Phe132Ser	missense_variant	5/5	2		ENSP00000446013.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

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

Jun 24, 2022

The c.395T>C (p.F132S) alteration is located in exon 5 (coding exon 4) of the VPS37C gene. This alteration results from a T to C substitution at nucleotide position 395, causing the phenylalanine (F) at amino acid position 132 to be replaced by a serine (S). 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	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.7	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.85		Gain of phosphorylation at F132 (P = 0.0218);Gain of phosphorylation at F132 (P = 0.0218);
MVP		0.86
MPC		0.57
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-60899965;