20-1571810-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006065.5(SIRPB1):c.661G>T(p.Val221Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SIRPB1 NM_006065.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.700

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17360577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRPB1	NM_006065.5	c.661G>T	p.Val221Phe	missense_variant	3/6	ENST00000381605.9
SIRPB1	XM_005260641.4	c.658G>T	p.Val220Phe	missense_variant	3/6
SIRPB1	NM_001083910.4	c.434-5543G>T		intron_variant
SIRPB1	NM_001330639.2	c.431-5543G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRPB1	ENST00000381605.9	c.661G>T	p.Val221Phe	missense_variant	3/6	1	NM_006065.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

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

Apr 26, 2023

The c.661G>T (p.V221F) alteration is located in exon 3 (coding exon 3) of the SIRPB1 gene. This alteration results from a G to T substitution at nucleotide position 661, causing the valine (V) at amino acid position 221 to be replaced by a phenylalanine (F). 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	0.18
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	12
Dann	Uncertain	0.99
DEOGEN2	Benign	0.019	T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Pathogenic	3.5	M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.066
Sift	Benign	0.059	T;T
Sift4G	Benign	0.11	T;D
Polyphen		1.0	D;.
Vest4		0.30
MutPred		0.40		Gain of catalytic residue at V221 (P = 0.0353);.;
MVP		0.17
MPC		0.38
ClinPred		0.82	D
GERP RS		-0.46
Varity_R		0.20
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-1552456;