20-1578340-C-T

Position:

chr20-1578340-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006065.5(SIRPB1):c.431G>A(p.Arg144His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,583,202 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00024 ( 2 hom., cov: 29)

Exomes 𝑓: 0.00024 ( 26 hom. )

Consequence

SIRPB1
NM_006065.5 missense, splice_region

Scores

Splicing: ADA: 0.00005694

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.459

Variant links:

Genes affected

SIRPB1 (HGNC:15928): (signal regulatory protein beta 1) 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 was found to interact with TYROBP/DAP12, a protein bearing immunoreceptor tyrosine-based activation motifs. This protein was also reported to participate in the recruitment of tyrosine kinase SYK. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2009]

SIRPB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009126037).

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SIRPB1	NM_006065.5 linkuse as main transcript	c.431G>A	p.Arg144His	missense_variant, splice_region_variant	2/6	ENST00000381605.9
SIRPB1	NM_001083910.4 linkuse as main transcript	c.431G>A	p.Arg144His	missense_variant, splice_region_variant	2/4
SIRPB1	NM_001330639.2 linkuse as main transcript	c.428G>A	p.Arg143His	missense_variant, splice_region_variant	2/4
SIRPB1	XM_005260641.4 linkuse as main transcript	c.428G>A	p.Arg143His	missense_variant, splice_region_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRPB1	ENST00000381605.9 linkuse as main transcript	c.431G>A	p.Arg144His	missense_variant, splice_region_variant	2/6	1	NM_006065.5		O00241-1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

147392

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000675

Gnomad ASJ

AF:

0.00586

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000848

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000106

Gnomad OTH

AF:

0.000502

GnomAD3 exomes

AF:

0.000380

AC:

AN:

247406

Hom.:

AF XY:

0.000381

AC XY:

AN XY:

133716

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00574

Gnomad EAS exome

AF:

0.000598

Gnomad SAS exome

AF:

0.000459

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000718

Gnomad OTH exome

AF:

0.000667

GnomAD4 exome

AF:

0.000235

AC:

338

AN:

1435692

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

169

AN XY:

714550

show subpopulations

Gnomad4 AFR exome

AF:

0.0000601

Gnomad4 AMR exome

AF:

0.0000450

Gnomad4 ASJ exome

AF:

0.00641

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.000583

Gnomad4 FIN exome

AF:

0.0000196

Gnomad4 NFE exome

AF:

0.0000633

Gnomad4 OTH exome

AF:

0.000589

GnomAD4 genome

AF:

0.000237

AC:

AN:

147510

Hom.:

Cov.:

AF XY:

0.000181

AC XY:

AN XY:

71718

show subpopulations

Gnomad4 AFR

AF:

0.0000245

Gnomad4 AMR

AF:

0.0000674

Gnomad4 ASJ

AF:

0.00586

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000849

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000106

Gnomad4 OTH

AF:

0.000496

Alfa

AF:

0.000616

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000472

AC:

ExAC

AF:

0.000366

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3468

EpiCase

AF:

0.000278

EpiControl

AF:

0.0000602

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

Jan 27, 2022

The c.431G>A (p.R144H) alteration is located in exon 2 (coding exon 2) of the SIRPB1 gene. This alteration results from a G to A substitution at nucleotide position 431, causing the arginine (R) at amino acid position 144 to be replaced by a histidine (H). 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

0.087

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.0088

.;.;T;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0077

LIST_S2

Benign

0.26

T;T;T;T;T;T

M_CAP

Benign

0.0033

MetaRNN

Benign

0.0079

T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.1

.;.;L;L;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.87

N;N;N;N;N;N

REVEL

Benign

0.016

Sift

Benign

0.65

T;T;T;T;T;T

Sift4G

Benign

0.57

T;T;T;T;T;T

Polyphen

0.19, 0.0020

.;.;B;B;.;.

Vest4

0.088, 0.054, 0.065, 0.080

MVP

0.030

MPC

0.16

ClinPred

0.0047

GERP RS

-1.2

Varity_R

0.10

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000057

dbscSNV1_RF

Benign

0.0020

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