20-1921445-C-G

Position:

• chr20-1921445-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001040023.2(SIRPA):​c.487C>G​(p.Gln163Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SIRPA NM_001040023.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.13

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037141412).
• BP6: Variant 20-1921445-C-G is Benign according to our data. Variant chr20-1921445-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2605307.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIRPA	NM_001040023.2	c.487C>G	p.Gln163Glu	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.487C>G	p.Gln163Glu	missense_variant	3/8	1	NM_001040023.2	ENSP00000351621.4
SIRPA	ENST00000356025.7	c.487C>G	p.Gln163Glu	missense_variant	4/9	1		ENSP00000348307.3
SIRPA	ENST00000400068.7	c.487C>G	p.Gln163Glu	missense_variant	4/9	1		ENSP00000382941.4
SIRPA	ENST00000622179.4	c.487C>G	p.Gln163Glu	missense_variant	4/9	5		ENSP00000478763.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461584 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727102

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.26
DANN	Benign	0.12
DEOGEN2	Benign	0.037	T;.;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00048	N
LIST_S2	Benign	0.035	T;T;.;.
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.037	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.74	N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	1.0	N;.;N;N
REVEL	Benign	0.039
Sift	Benign	0.87	T;.;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.13
MutPred		0.31		Gain of disorder (P = 0.0842);Gain of disorder (P = 0.0842);Gain of disorder (P = 0.0842);Gain of disorder (P = 0.0842);
MVP		0.24
MPC		1.5
ClinPred		0.016	T
GERP RS		1.3
Varity_R		0.19
gMVP		0.53

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: rs202077577; hg19: chr20-1902091; COSMIC: COSV100605115;