20-1921559-G-A

Position:

chr20-1921559-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001040023.2(SIRPA):c.601G>A(p.Val201Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,614,210 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 35 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 43 hom. )

Consequence

SIRPA
NM_001040023.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.428

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019869506).

BP6

Variant 20-1921559-G-A is Benign according to our data. Variant chr20-1921559-G-A is described in ClinVar as [Benign]. Clinvar id is 714812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0125 (1903/152328) while in subpopulation AFR AF= 0.0434 (1802/41566). AF 95% confidence interval is 0.0417. There are 35 homozygotes in gnomad4. There are 904 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 35 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIRPA	NM_001040023.2 linkuse as main transcript	c.601G>A	p.Val201Ile	missense_variant	3/8	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.601G>A	p.Val201Ile	missense_variant	3/8	1	NM_001040023.2	ENSP00000351621.4	P78324-1
SIRPA	ENST00000356025.7 linkuse as main transcript	c.601G>A	p.Val201Ile	missense_variant	4/9	1		ENSP00000348307.3	P78324-1
SIRPA	ENST00000400068.7 linkuse as main transcript	c.601G>A	p.Val201Ile	missense_variant	4/9	1		ENSP00000382941.4	P78324-1
SIRPA	ENST00000622179.4 linkuse as main transcript	c.601G>A	p.Val201Ile	missense_variant	4/9	5		ENSP00000478763.1	P78324-2

Frequencies

GnomAD3 genomes

AF:

0.0125

AC:

1900

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00425

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.0119

GnomAD3 exomes

AF:

0.00354

AC:

891

AN:

251496

Hom.:

AF XY:

0.00260

AC XY:

354

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0471

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000369

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.00140

AC:

2049

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

906

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0473

Gnomad4 AMR exome

AF:

0.00224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000464

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000129

Gnomad4 OTH exome

AF:

0.00273

GnomAD4 genome

AF:

0.0125

AC:

1903

AN:

152328

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

904

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0434

Gnomad4 AMR

AF:

0.00425

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.00274

Hom.:

Bravo

AF:

0.0143

ESP6500AA

AF:

0.0374

AC:

165

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00440

AC:

534

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.79

CADD

Benign

7.2

DANN

Benign

0.87

DEOGEN2

Benign

0.023

T;.;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.0077

T;T;.;.

MetaRNN

Benign

0.0020

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.69

N;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.74

N;.;N;N

REVEL

Benign

0.015

Sift

Benign

0.18

T;.;T;T

Sift4G

Benign

0.13

T;T;T;T

Polyphen

0.0010

B;B;B;B

Vest4

0.098

MVP

0.27

MPC

1.2

ClinPred

0.0024

GERP RS

-5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.15

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