20-1571722-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006065.5(SIRPB1):c.749G>A(p.Arg250Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 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 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: SIRPB1 NM_006065.5 missense, splice_region
• Scores: Splicing: ADA: 0.0001321
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.798

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018906564).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRPB1	NM_006065.5	c.749G>A	p.Arg250Gln	missense_variant, splice_region_variant	3/6	ENST00000381605.9
SIRPB1	XM_005260641.4	c.746G>A	p.Arg249Gln	missense_variant, splice_region_variant	3/6
SIRPB1	NM_001083910.4	c.434-5455G>A		intron_variant
SIRPB1	NM_001330639.2	c.431-5455G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRPB1	ENST00000381605.9	c.749G>A	p.Arg250Gln	missense_variant, splice_region_variant	3/6	1	NM_006065.5

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 37 AN: 251412 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135878

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000971 AC: 142 AN: 1461886 Hom.: 0 Cov.: 35 AF XY: 0.0000935 AC XY: 68 AN XY: 727246

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.0000894

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: 0.0000962

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74464

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000266 Hom.: 0

Bravo AF: 0.000453

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2021

The c.749G>A (p.R250Q) alteration is located in exon 3 (coding exon 3) of the SIRPB1 gene. This alteration results from a G to A substitution at nucleotide position 749, causing the arginine (R) at amino acid position 250 to be replaced by a glutamine (Q). 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	0.097
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.032	T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.019	T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.1	N;D
REVEL	Benign	0.17
Sift	Benign	0.34	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.92	P;.
Vest4		0.32
MVP		0.14
MPC		0.15
ClinPred		0.045	T
GERP RS		-0.65
Varity_R		0.048
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0
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: rs144175019; hg19: chr20-1552368; COSMIC: COSV53537965;