dbSNP rs539268857: SIRPA:p.Pro74Ala (chr20-1915239-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001040023.2(SIRPA):c.220C>G(p.Pro74Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,611,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P74S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 27)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SIRPA
NM_001040023.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.684

Variant links:

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]

SIRPA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.2833391).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIRPA	NM_001040023.2 link	c.220C>G	p.Pro74Ala	missense_variant	Exon 2 of 8	ENST00000358771.5	NP_001035112.1	P78324-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIRPA	ENST00000358771.5 link	c.220C>G	p.Pro74Ala	missense_variant	Exon 2 of 8	1	NM_001040023.2	ENSP00000351621.4	P78324-1
SIRPA	ENST00000356025.7 link	c.220C>G	p.Pro74Ala	missense_variant	Exon 3 of 9	1		ENSP00000348307.3	P78324-1
SIRPA	ENST00000400068.7 link	c.220C>G	p.Pro74Ala	missense_variant	Exon 3 of 9	1		ENSP00000382941.4	P78324-1
SIRPA	ENST00000622179.4 link	c.220C>G	p.Pro74Ala	missense_variant	Exon 3 of 9	5		ENSP00000478763.1	P78324-2

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

149920

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000491

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000203

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250122

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135306

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461478

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727030

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000267

AC:

AN:

149920

Hom.:

Cov.:

AF XY:

0.0000411

AC XY:

AN XY:

72962

show subpopulations

Gnomad4 AFR

AF:

0.0000491

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000203

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.39

T;.;T;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.57

T;T;.;.

M_CAP

Benign

0.0050

MetaRNN

Benign

0.28

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M;M;M

PrimateAI

Benign

0.24

PROVEAN

Pathogenic

-5.0

D;.;D;D

REVEL

Benign

0.12

Sift

Uncertain

0.024

D;.;D;D

Sift4G

Uncertain

0.040

D;D;D;D

Polyphen

0.0050

B;B;B;B

Vest4

0.32

MVP

0.37

MPC

0.52

ClinPred

0.043

GERP RS

3.1

Varity_R

0.44

gMVP

0.23

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over