20-1571944-G-A

Position:

• chr20-1571944-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006065.5(SIRPB1):​c.527C>T​(p.Pro176Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SIRPB1 NM_006065.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.00

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]

ENSG00000260861 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIRPB1	NM_006065.5	c.527C>T	p.Pro176Leu	missense_variant	3/6	ENST00000381605.9	NP_006056.2
SIRPB1	XM_005260641.4	c.524C>T	p.Pro175Leu	missense_variant	3/6		XP_005260698.1
SIRPB1	NM_001083910.4	c.434-5677C>T		intron_variant			NP_001077379.1
SIRPB1	NM_001330639.2	c.431-5677C>T		intron_variant			NP_001317568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIRPB1	ENST00000381605.9	c.527C>T	p.Pro176Leu	missense_variant	3/6	1	NM_006065.5	ENSP00000371018.5
ENSG00000260861	ENST00000564763.1	c.433+6394C>T		intron_variant		4		ENSP00000457944.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Nov 11, 2024

The c.527C>T (p.P176L) alteration is located in exon 3 (coding exon 3) of the SIRPB1 gene. This alteration results from a C to T substitution at nucleotide position 527, causing the proline (P) at amino acid position 176 to be replaced by a leucine (L). 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	Uncertain	0.44
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	-0.032
FATHMM_MKL	Benign	0.40	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.0030	T
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	4.5	H
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-8.9	D
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.83		Loss of disorder (P = 0.0612);
MVP		0.45
MPC		0.59
ClinPred		1.0	D
GERP RS		1.4
Varity_R		0.58
gMVP		0.73

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: chr20-1552590;