10-49107993-C-A

Variant summary

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

The NM_001031746.5(VSTM4):c.58G>T(p.Val20Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: VSTM4 NM_001031746.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.397

Genes affected

VSTM4 (HGNC:26470): (V-set and transmembrane domain containing 4) Predicted to act upstream of or within several processes, including endothelial cell migration; retina blood vessel maintenance; and vasculature development. Predicted to be located in extracellular region and plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.2800048).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VSTM4	NM_001031746.5	c.58G>T	p.Val20Phe	missense_variant, splice_region_variant	2/8	ENST00000332853.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VSTM4	ENST00000332853.9	c.58G>T	p.Val20Phe	missense_variant, splice_region_variant	2/8	1	NM_001031746.5	P1
VSTM4	ENST00000298454.3	c.58G>T	p.Val20Phe	missense_variant, splice_region_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1412234 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 697426

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: 9.22e-7

Gnomad4 OTH exome AF: 0.00

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

Jan 03, 2024

The c.58G>T (p.V20F) alteration is located in exon 2 (coding exon 2) of the VSTM4 gene. This alteration results from a G to T substitution at nucleotide position 58, causing the valine (V) at amino acid position 20 to be replaced by a phenylalanine (F). 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	0.16
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.88	P;D
Vest4		0.46
MutPred		0.47		Gain of catalytic residue at P18 (P = 0.1578);Gain of catalytic residue at P18 (P = 0.1578);
MVP		0.43
MPC		0.23
ClinPred		0.93	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.62

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: chr10-50316038;