rs2243603

Positions:

• chr20-1566265-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006065.5(SIRPB1):​c.1087G>C​(p.Ala363Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.773 in 1,591,648 control chromosomes in the GnomAD database, including 477,469 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.80 (49363 hom., cov: 31)
  • Exomes 𝑓: 0.77 (428106 hom.)
• Consequence: SIRPB1 NM_006065.5 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.156

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.500686E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRPB1	NM_006065.5	c.1087G>C	p.Ala363Pro	missense_variant, splice_region_variant	5/6	ENST00000381605.9
SIRPB1	NM_001083910.4	c.436G>C	p.Ala146Pro	missense_variant, splice_region_variant	3/4
SIRPB1	NM_001330639.2	c.433G>C	p.Ala145Pro	missense_variant, splice_region_variant	3/4
SIRPB1	XM_005260641.4	c.1084G>C	p.Ala362Pro	missense_variant, splice_region_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRPB1	ENST00000381605.9	c.1087G>C	p.Ala363Pro	missense_variant, splice_region_variant	5/6	1	NM_006065.5

Frequencies

GnomAD3 genomes AF: 0.802 AC: 121868 AN: 152028 Hom.: 49314 Cov.: 31

Gnomad AFR AF: 0.910

Gnomad AMI AF: 0.741

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.740

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.760

Gnomad FIN AF: 0.801

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.771

Gnomad OTH AF: 0.785

GnomAD3 exomes AF: 0.772 AC: 168748 AN: 218702 Hom.: 65557 AF XY: 0.774 AC XY: 91010 AN XY: 117570

Gnomad AFR exome AF: 0.915

Gnomad AMR exome AF: 0.626

Gnomad ASJ exome AF: 0.744

Gnomad EAS exome AF: 0.821

Gnomad SAS exome AF: 0.774

Gnomad FIN exome AF: 0.797

Gnomad NFE exome AF: 0.784

Gnomad OTH exome AF: 0.773

GnomAD4 exome AF: 0.770 AC: 1108839 AN: 1439502 Hom.: 428106 Cov.: 29 AF XY: 0.771 AC XY: 550473 AN XY: 714392

Gnomad4 AFR exome AF: 0.918

Gnomad4 AMR exome AF: 0.631

Gnomad4 ASJ exome AF: 0.735

Gnomad4 EAS exome AF: 0.788

Gnomad4 SAS exome AF: 0.762

Gnomad4 FIN exome AF: 0.794

Gnomad4 NFE exome AF: 0.770

Gnomad4 OTH exome AF: 0.782

GnomAD4 genome AF: 0.802 AC: 121967 AN: 152146 Hom.: 49363 Cov.: 31 AF XY: 0.799 AC XY: 59395 AN XY: 74354

Gnomad4 AFR AF: 0.910

Gnomad4 AMR AF: 0.678

Gnomad4 ASJ AF: 0.740

Gnomad4 EAS AF: 0.800

Gnomad4 SAS AF: 0.759

Gnomad4 FIN AF: 0.801

Gnomad4 NFE AF: 0.771

Gnomad4 OTH AF: 0.787

Alfa AF: 0.777 Hom.: 33913

Bravo AF: 0.799

TwinsUK AF: 0.767 AC: 2845

ALSPAC AF: 0.763 AC: 2939

ESP6500AA AF: 0.903 AC: 3979

ESP6500EA AF: 0.773 AC: 6645

ExAC AF: 0.762 AC: 91819

Asia WGS AF: 0.801 AC: 2785 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.7
DANN	Benign	0.54
DEOGEN2	Benign	0.0030	T;.;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.00013	N
LIST_S2	Benign	0.33	T;T;T;T;T
MetaRNN	Benign	9.1e-7	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.8	N;.;.;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.27	N;N;N;N;N
REVEL	Benign	0.025
Sift	Benign	0.28	T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.0	B;B;.;.;.
Vest4		0.10
MPC		0.17
ClinPred		0.0027	T
GERP RS		-3.1
Varity_R		0.17
gMVP		0.17

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: rs2243603; hg19: chr20-1546911; COSMIC: COSV53538817; COSMIC: COSV53538817;