rs3746721

Variant names:

• chr20-1630248-G-A
• rs3746721
• NM_018556.4:c.1140C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_018556.4(SIRPG):​c.1140C>T​(p.Tyr380Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,569,130 control chromosomes in the GnomAD database, including 59,925 homozygotes. 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: 𝑓 0.24 (5274 hom., cov: 31)
  • Exomes 𝑓: 0.26 (54651 hom.)
• Consequence: SIRPG NM_018556.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.70
• Publications: 17 publications found

Genes affected

SIRPG (HGNC:15757): (signal regulatory protein gamma) 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. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

SIRPG Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: LIMITED Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP7: Synonymous conserved (PhyloP=-1.7 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIRPG	NM_018556.4	c.1140C>T	p.Tyr380Tyr	synonymous_variant	Exon 5 of 6	ENST00000303415.7	NP_061026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIRPG	ENST00000303415.7	c.1140C>T	p.Tyr380Tyr	synonymous_variant	Exon 5 of 6	1	NM_018556.4	ENSP00000305529.3

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36364 AN: 151846 Hom.: 5279 Cov.: 31

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.480

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.279

GnomAD2 exomes AF: 0.302 AC: 57237 AN: 189316 AF XY: 0.313

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.293

Gnomad ASJ exome AF: 0.343

Gnomad EAS exome AF: 0.599

Gnomad FIN exome AF: 0.258

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.303

GnomAD4 exome AF: 0.263 AC: 372430 AN: 1417164 Hom.: 54651 Cov.: 32 AF XY: 0.270 AC XY: 189025 AN XY: 701004

African (AFR) AF: 0.112 AC: 3675 AN: 32812

American (AMR) AF: 0.289 AC: 11159 AN: 38648

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 8798 AN: 25346

East Asian (EAS) AF: 0.586 AC: 22157 AN: 37818

South Asian (SAS) AF: 0.456 AC: 36800 AN: 80692

European-Finnish (FIN) AF: 0.266 AC: 13402 AN: 50444

Middle Eastern (MID) AF: 0.387 AC: 2077 AN: 5370

European-Non Finnish (NFE) AF: 0.237 AC: 257683 AN: 1087296

Other (OTH) AF: 0.284 AC: 16679 AN: 58738

GnomAD4 genome AF: 0.239 AC: 36369 AN: 151966 Hom.: 5274 Cov.: 31 AF XY: 0.246 AC XY: 18306 AN XY: 74274

African (AFR) AF: 0.119 AC: 4953 AN: 41460

American (AMR) AF: 0.275 AC: 4197 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1268 AN: 3472

East Asian (EAS) AF: 0.606 AC: 3119 AN: 5148

South Asian (SAS) AF: 0.477 AC: 2292 AN: 4800

European-Finnish (FIN) AF: 0.256 AC: 2704 AN: 10566

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 16975 AN: 67926

Other (OTH) AF: 0.281 AC: 593 AN: 2114

Alfa AF: 0.252 Hom.: 18085

Bravo AF: 0.232

Asia WGS AF: 0.519 AC: 1804 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.71
DANN	Benign	0.50
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3746721; hg19: chr20-1610894; COSMIC: COSV53807023; COSMIC: COSV53807023;