20-1921454-G-C

Position:

• chr20-1921454-G-C

Variant summary

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

The NM_001040023.2(SIRPA):​c.496G>C​(p.Val166Leu) 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: 32)
• Consequence: SIRPA NM_001040023.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.75

Genes affected

SIRPA (HGNC:9662): (signal regulatory protein alpha) 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. This protein can be phosphorylated by tyrosine kinases. The phospho-tyrosine residues of this PTP have been shown to recruit SH2 domain containing tyrosine phosphatases (PTP), and serve as substrates of PTPs. This protein was found to participate in signal transduction mediated by various growth factor receptors. CD47 has been demonstrated to be a ligand for this receptor protein. This gene and its product share very high similarity with several other members of the SIRP family. These related genes are located in close proximity to each other on chromosome 20p13. Multiple alternatively spliced transcript variants have been determined for this gene. [provided by RefSeq, Jul 2008]

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, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIRPA	NM_001040023.2	c.496G>C	p.Val166Leu	missense_variant	3/8	ENST00000358771.5	NP_001035112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIRPA	ENST00000358771.5	c.496G>C	p.Val166Leu	missense_variant	3/8	1	NM_001040023.2	ENSP00000351621.4
SIRPA	ENST00000356025.7	c.496G>C	p.Val166Leu	missense_variant	4/9	1		ENSP00000348307.3
SIRPA	ENST00000400068.7	c.496G>C	p.Val166Leu	missense_variant	4/9	1		ENSP00000382941.4
SIRPA	ENST00000622179.4	c.496G>C	p.Val166Leu	missense_variant	4/9	5		ENSP00000478763.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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

Aug 28, 2023

The c.496G>C (p.V166L) alteration is located in exon 4 (coding exon 3) of the SIRPA gene. This alteration results from a G to C substitution at nucleotide position 496, causing the valine (V) at amino acid position 166 to be replaced by a leucine (L). 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	0.22
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;T;T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.94	D;D;.;.
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;M;M;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.5	N;.;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D;.;D;D
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		0.98	D;B;D;D
Vest4		0.63
MutPred		0.77		Loss of glycosylation at T165 (P = 0.0823);Loss of glycosylation at T165 (P = 0.0823);Loss of glycosylation at T165 (P = 0.0823);Loss of glycosylation at T165 (P = 0.0823);
MVP		0.62
MPC		1.7
ClinPred		0.87	D
GERP RS		4.4
Varity_R		0.53
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr20-1902100;