X-66027520-G-C

Position:

• chrX-66027520-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007268.3(VSIG4):​c.764C>G​(p.Ser255Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000556 in 1,078,242 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000056 (0 hom. 1 hem.)
• Consequence: VSIG4 NM_007268.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11

Genes affected

VSIG4 (HGNC:17032): (V-set and immunoglobulin domain containing 4) This gene encodes a v-set and immunoglobulin-domain containing protein that is structurally related to the B7 family of immune regulatory proteins. The encoded protein may be a negative regulator of T-cell responses. This protein is also a receptor for the complement component 3 fragments C3b and iC3b. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15928999).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VSIG4	NM_007268.3	c.764C>G	p.Ser255Cys	missense_variant	5/8	ENST00000374737.9	NP_009199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VSIG4	ENST00000374737.9	c.764C>G	p.Ser255Cys	missense_variant	5/8	1	NM_007268.3	ENSP00000363869.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000556 AC: 6 AN: 1078242 Hom.: 0 Cov.: 28 AF XY: 0.00000288 AC XY: 1 AN XY: 346852

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: 0.00000724

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

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

Feb 27, 2024

The c.764C>G (p.S255C) alteration is located in exon 5 (coding exon 5) of the VSIG4 gene. This alteration results from a C to G substitution at nucleotide position 764, causing the serine (S) at amino acid position 255 to be replaced by a cysteine (C). 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	0.17
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.075	T;.;.
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;L;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.094
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.021	D;T;D
Polyphen		0.98	D;D;D
Vest4		0.40
MVP		0.067
MPC		0.012
ClinPred		0.30	T
GERP RS		2.1
Varity_R		0.14
gMVP		0.31

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: rs141926571; hg19: chrX-65247362;