17-4785510-C-T

Position:

• chr17-4785510-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_182566.3(VMO1):​c.461G>A​(p.Gly154Glu) variant causes a missense change. 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: 33)
• Consequence: VMO1 NM_182566.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82

Genes affected

VMO1 (HGNC:30387): (vitelline membrane outer layer 1 homolog) Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VMO1	NM_182566.3	c.461G>A	p.Gly154Glu	missense_variant	3/3	ENST00000328739.6	NP_872372.1
VMO1	NM_001144939.2	c.*152G>A		3_prime_UTR_variant	3/3		NP_001138411.1
VMO1	NM_001144940.2	c.*132G>A		3_prime_UTR_variant	3/3		NP_001138412.1
VMO1	NM_001144941.2	c.*132G>A		3_prime_UTR_variant	2/2		NP_001138413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VMO1	ENST00000328739.6	c.461G>A	p.Gly154Glu	missense_variant	3/3	1	NM_182566.3	ENSP00000328397	P1
VMO1	ENST00000354194.4	c.*132G>A		3_prime_UTR_variant	2/2	1		ENSP00000346133
VMO1	ENST00000416307.6	c.*132G>A		3_prime_UTR_variant	3/3	2		ENSP00000390450
VMO1	ENST00000441199.2	c.*152G>A		3_prime_UTR_variant	3/3	2		ENSP00000408166

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Nov 21, 2022

The c.461G>A (p.G154E) alteration is located in exon 3 (coding exon 3) of the VMO1 gene. This alteration results from a G to A substitution at nucleotide position 461, causing the glycine (G) at amino acid position 154 to be replaced by a glutamic acid (E). 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	0.77
BayesDel_addAF	Benign	-0.0075	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.75		Gain of solvent accessibility (P = 0.0062);
MVP		0.55
MPC		1.5
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.75
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs758875205; hg19: chr17-4688805;