17-4785391-C-A

Position:

• chr17-4785391-C-A

Variant summary

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

The ENST00000328739.6(VMO1):​c.580G>T​(p.Asp194Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,272 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VMO1 ENST00000328739.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.75

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 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, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VMO1	NM_182566.3	c.580G>T	p.Asp194Tyr	missense_variant	3/3	ENST00000328739.6	NP_872372.1
VMO1	NM_001144939.2	c.*271G>T		3_prime_UTR_variant	3/3		NP_001138411.1
VMO1	NM_001144940.2	c.*251G>T		3_prime_UTR_variant	3/3		NP_001138412.1
VMO1	NM_001144941.2	c.*251G>T		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.580G>T	p.Asp194Tyr	missense_variant	3/3	1	NM_182566.3	ENSP00000328397.5
VMO1	ENST00000354194.4	c.*251G>T		3_prime_UTR_variant	2/2	1		ENSP00000346133.4
VMO1	ENST00000441199.2	c.*271G>T		3_prime_UTR_variant	3/3	2		ENSP00000408166.2
VMO1	ENST00000416307.6	c.*251G>T		3_prime_UTR_variant	3/3	2		ENSP00000390450.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458272 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724964

Gnomad4 AFR exome AF: 0.00

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: 9.01e-7

Gnomad4 OTH exome AF: 0.0000166

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

Oct 06, 2021

The c.580G>T (p.D194Y) alteration is located in exon 3 (coding exon 3) of the VMO1 gene. This alteration results from a G to T substitution at nucleotide position 580, causing the aspartic acid (D) at amino acid position 194 to be replaced by a tyrosine (Y). 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	0.72
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.74		Loss of disorder (P = 0.0026);
MVP		0.77
MPC		1.5
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.92

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: chr17-4688686;