20-1922415-C-G

Position:

chr20-1922415-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001040023.2(SIRPA):c.857C>G(p.Thr286Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,258 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 1 hom. )

Consequence

SIRPA
NM_001040023.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0560

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14454597).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIRPA	NM_001040023.2 linkuse as main transcript	c.857C>G	p.Thr286Ser	missense_variant	4/8	ENST00000358771.5	NP_001035112.1	P78324-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SIRPA	ENST00000358771.5 linkuse as main transcript	c.857C>G	p.Thr286Ser	missense_variant	4/8	1	NM_001040023.2	ENSP00000351621.4	P78324-1
SIRPA	ENST00000356025.7 linkuse as main transcript	c.857C>G	p.Thr286Ser	missense_variant	5/9	1		ENSP00000348307.3	P78324-1
SIRPA	ENST00000400068.7 linkuse as main transcript	c.857C>G	p.Thr286Ser	missense_variant	5/9	1		ENSP00000382941.4	P78324-1
SIRPA	ENST00000622179.4 linkuse as main transcript	c.857C>G	p.Thr286Ser	missense_variant	5/9	5		ENSP00000478763.1	P78324-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

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:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251488

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727248

show subpopulations

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:

0.000278

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2023

The c.857C>G (p.T286S) alteration is located in exon 5 (coding exon 4) of the SIRPA gene. This alteration results from a C to G substitution at nucleotide position 857, causing the threonine (T) at amino acid position 286 to be replaced by a serine (S). 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

0.12

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.065

T;.;T;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.68

T;T;.;.

M_CAP

Benign

0.0096

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.9

L;L;L;L

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.6

D;.;D;D

REVEL

Benign

0.13

Sift

Benign

0.28

T;.;T;T

Sift4G

Benign

0.43

T;T;T;T

Polyphen

0.12

B;B;B;B

Vest4

0.11

MutPred

0.53

Gain of disorder (P = 0.1083);Gain of disorder (P = 0.1083);Gain of disorder (P = 0.1083);Gain of disorder (P = 0.1083);

MVP

0.35

MPC

0.87

ClinPred

0.16

GERP RS

-2.0

Varity_R

0.31

gMVP

0.37

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over