chr20-1937841-G-A

Variant names:

• chr20-1937841-G-A
• rs3197744
• NM_001040023.2:c.*273G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001040023.2(SIRPA):​c.*273G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000292 in 341,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: SIRPA NM_001040023.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.661
• Publications: 0 publications found

Genes affected

SIRPA (HGNC:9662): (signal regulatory protein alpha) 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 can be phosphorylated by tyrosine kinases. The phospho-tyrosine residues of this PTP have been shown to recruit SH2 domain containing tyrosine phosphatases (PTP), and serve as substrates of PTPs. This protein was found to participate in signal transduction mediated by various growth factor receptors. CD47 has been demonstrated to be a ligand for this receptor protein. This gene and its product share very high similarity with several other members of the SIRP family. These related genes are located in close proximity to each other on chromosome 20p13. Multiple alternatively spliced transcript variants have been determined for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIRPA	NM_001040023.2	c.*273G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000358771.5	NP_001035112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIRPA	ENST00000358771.5	c.*273G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_001040023.2	ENSP00000351621.4
SIRPA	ENST00000356025.7	c.*273G>A		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000348307.3
SIRPA	ENST00000400068.7	c.*273G>A		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000382941.4
SIRPA	ENST00000622179.4	c.*273G>A		3_prime_UTR_variant	Exon 9 of 9	5		ENSP00000478763.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000292 AC: 1 AN: 341984 Hom.: 0 Cov.: 3 AF XY: 0.00000566 AC XY: 1 AN XY: 176564

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 10896

American (AMR) AF: 0.00 AC: 0 AN: 15052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11172

East Asian (EAS) AF: 0.00 AC: 0 AN: 25810

South Asian (SAS) AF: 0.0000336 AC: 1 AN: 29788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1564

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 204738

Other (OTH) AF: 0.00 AC: 0 AN: 20752

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.90
DANN	Benign	0.84
PhyloP100		-0.66

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

Other links and lift over

dbSNP: rs3197744; hg19: chr20-1918487;