20-1649124-C-T

Variant summary

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

The NM_018556.4(SIRPG):c.358G>A(p.Val120Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,696 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SIRPG NM_018556.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44

Genes affected

SIRPG (HGNC:15757): (signal regulatory protein gamma) The protein encoded by this gene is a member of the signal-regulatory protein (SIRP) family, and also belongs to the immunoglobulin superfamily. SIRP family members are receptor-type transmembrane glycoproteins known to be involved in the negative regulation of receptor tyrosine kinase-coupled signaling processes. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRPG	NM_018556.4	c.358G>A	p.Val120Met	missense_variant	2/6	ENST00000303415.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRPG	ENST00000303415.7	c.358G>A	p.Val120Met	missense_variant	2/6	1	NM_018556.4	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461696 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727156

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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 04, 2024

The c.358G>A (p.V120M) alteration is located in exon 2 (coding exon 2) of the SIRPG gene. This alteration results from a G to A substitution at nucleotide position 358, causing the valine (V) at amino acid position 120 to be replaced by a methionine (M). 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	0.30
BayesDel_addAF	Benign	0.00061	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.89	D;T;D;D;.
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.48	T;T;T;T;T
MetaSVM	Benign	-0.28	T
MutationTaster	Benign	0.85	D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.023	D;D;T;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		1.0	.;D;D;D;D
Vest4		0.40
MutPred		0.71		.;Gain of disorder (P = 0.0781);Gain of disorder (P = 0.0781);Gain of disorder (P = 0.0781);Gain of disorder (P = 0.0781);
MVP		0.68
MPC		0.18
ClinPred		1.0	D
GERP RS		1.9
Varity_R		0.34
gMVP		0.52

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: rs1410520246; hg19: chr20-1629770;