20-1578470-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_006065.5(SIRPB1):c.301C>A(p.Leu101Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000267 in 145,914 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (3 hom., cov: 29)
  • Exomes 𝑓: 0.00043 (69 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIRPB1 NM_006065.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.977

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02264741).
• BP6: Variant 20-1578470-G-T is Benign according to our data. Variant chr20-1578470-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2342658.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRPB1	NM_006065.5	c.301C>A	p.Leu101Met	missense_variant	2/6	ENST00000381605.9
SIRPB1	NM_001083910.4	c.301C>A	p.Leu101Met	missense_variant	2/4
SIRPB1	NM_001330639.2	c.298C>A	p.Leu100Met	missense_variant	2/4
SIRPB1	XM_005260641.4	c.298C>A	p.Leu100Met	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRPB1	ENST00000381605.9	c.301C>A	p.Leu101Met	missense_variant	2/6	1	NM_006065.5

Frequencies

GnomAD3 genomes AF: 0.000233 AC: 34 AN: 145790 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.000522

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000214

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00694

Gnomad NFE AF: 0.000123

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000847 AC: 21 AN: 247878 Hom.: 1 AF XY: 0.0000821 AC XY: 11 AN XY: 133976

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000485

Gnomad NFE exome AF: 0.0000626

Gnomad OTH exome AF: 0.000333

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000429 AC: 593 AN: 1382496 Hom.: 69 Cov.: 33 AF XY: 0.000444 AC XY: 306 AN XY: 689742

Gnomad4 AFR exome AF: 0.00113

Gnomad4 AMR exome AF: 0.000205

Gnomad4 ASJ exome AF: 0.000118

Gnomad4 EAS exome AF: 0.0000510

Gnomad4 SAS exome AF: 0.000190

Gnomad4 FIN exome AF: 0.000611

Gnomad4 NFE exome AF: 0.000429

Gnomad4 OTH exome AF: 0.000763

GnomAD4 genome AF: 0.000267 AC: 39 AN: 145914 Hom.: 3 Cov.: 29 AF XY: 0.000296 AC XY: 21 AN XY: 70896

Gnomad4 AFR AF: 0.000644

Gnomad4 AMR AF: 0.000136

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000215

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000123

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000190 Hom.: 0

ExAC AF: 0.000432 AC: 52

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.014
Dann	Benign	0.13
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00074	N
LIST_S2	Benign	0.19	T;T;T;T;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.023	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.95	N;N;N;N;N;N
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T;T
Polyphen		0.0	.;.;B;B;.;.
Vest4		0.090, 0.088, 0.13, 0.13
MVP		0.072
MPC		0.12
ClinPred		0.049	T
GERP RS		-0.32
Varity_R		0.23
gMVP		0.23

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: rs111353945; hg19: chr20-1559116;