7-55492355-C-T

Position:

• chr7-55492355-C-T

Variant summary

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

The ENST00000285279.10(VOPP1):​c.255G>A​(p.Met85Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,456,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: VOPP1 ENST00000285279.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.24

Genes affected

VOPP1 (HGNC:34518): (VOPP1 WW domain binding protein) Located in cytoplasmic vesicle membrane and endosome. Is integral component of organelle membrane. [provided by Alliance of Genome Resources, Apr 2022]

VOPP1 (HGNC:):

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=0.28960973).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VOPP1	NM_030796.5	c.255G>A	p.Met85Ile	missense_variant	4/5	ENST00000285279.10	NP_110423.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VOPP1	ENST00000285279.10	c.255G>A	p.Met85Ile	missense_variant	4/5	1	NM_030796.5	ENSP00000285279.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456092 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 723812

Gnomad4 AFR exome AF: 0.0000300

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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 14, 2022

The c.255G>A (p.M85I) alteration is located in exon 4 (coding exon 4) of the VOPP1 gene. This alteration results from a G to A substitution at nucleotide position 255, causing the methionine (M) at amino acid position 85 to be replaced by an isoleucine (I). 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	Uncertain	0.55
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D;D;.;.;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.1	N;N;D;D;.;N;D;D;N;D;D;D;D
REVEL	Benign	0.067
Sift	Benign	0.14	T;T;T;T;.;T;T;T;T;T;T;T;.
Sift4G	Benign	0.33	T;T;T;T;T;T;.;T;T;T;.;.;.
Polyphen		0.0070	B;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.34
MutPred		0.25		Gain of catalytic residue at M85 (P = 0.0233);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.21
MPC		0.23
ClinPred		0.78	D
GERP RS		4.5
Varity_R		0.26
gMVP		0.66

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: rs1793637431; hg19: chr7-55560048;