20-1921718-A-G

Position:

• chr20-1921718-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001040023.2(SIRPA):​c.754+6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,579,406 control chromosomes in the GnomAD database, including 473 homozygotes. In-silico tool predicts 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (32 hom., cov: 32)
  • Exomes 𝑓: 0.012 (441 hom.)
• Consequence: SIRPA NM_001040023.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003557
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.70

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 20-1921718-A-G is Benign according to our data. Variant chr20-1921718-A-G is described in ClinVar as [Benign]. Clinvar id is 771046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0169 (2568/151936) while in subpopulation NFE AF= 0.0253 (1716/67784). AF 95% confidence interval is 0.0243. There are 32 homozygotes in gnomad4. There are 1179 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 32 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIRPA	NM_001040023.2	c.754+6A>G		splice_region_variant, intron_variant		ENST00000358771.5	NP_001035112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIRPA	ENST00000358771.5	c.754+6A>G		splice_region_variant, intron_variant		1	NM_001040023.2	ENSP00000351621.4
SIRPA	ENST00000356025.7	c.754+6A>G		splice_region_variant, intron_variant		1		ENSP00000348307.3
SIRPA	ENST00000400068.7	c.754+6A>G		splice_region_variant, intron_variant		1		ENSP00000382941.4
SIRPA	ENST00000622179.4	c.754+6A>G		splice_region_variant, intron_variant		5		ENSP00000478763.1

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2565 AN: 151818 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00534

Gnomad AMI AF: 0.0982

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.0289

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0146

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0253

Gnomad OTH AF: 0.0211

GnomAD3 exomes AF: 0.0114 AC: 2836 AN: 248008 Hom.: 42 AF XY: 0.0115 AC XY: 1544 AN XY: 133836

Gnomad AFR exome AF: 0.00278

Gnomad AMR exome AF: 0.0124

Gnomad ASJ exome AF: 0.0193

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0116

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0213

GnomAD4 exome AF: 0.0123 AC: 17529 AN: 1427470 Hom.: 441 Cov.: 34 AF XY: 0.0125 AC XY: 8880 AN XY: 710810

Gnomad4 AFR exome AF: 0.00300

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.0231

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0127

Gnomad4 FIN exome AF: 0.00360

Gnomad4 NFE exome AF: 0.0128

Gnomad4 OTH exome AF: 0.0162

GnomAD4 genome AF: 0.0169 AC: 2568 AN: 151936 Hom.: 32 Cov.: 32 AF XY: 0.0159 AC XY: 1179 AN XY: 74276

Gnomad4 AFR AF: 0.00537

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.0289

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0148

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.0253

Gnomad4 OTH AF: 0.0209

Alfa AF: 0.0232 Hom.: 9

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.4
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.13
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: rs149287513; hg19: chr20-1902364;