20-1635269-G-C

Variant names:

• chr20-1635269-G-C
• rs547634798
• NM_018556.4:c.1079C>G

Variant summary

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

The NM_018556.4(SIRPG):​c.1079C>G​(p.Pro360Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SIRPG NM_018556.4 missense, splice_region
• Scores: Splicing: ADA: 0.0009402
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.93
• Publications: 0 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-AS1 (HGNC:51229): (SIRPG antisense RNA 1)

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 (MetaRNN=0.053117782).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018556.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRPG	NM_018556.4	MANE Select	c.1079C>G	p.Pro360Arg	missense splice_region	Exon 4 of 6	NP_061026.2	Q9P1W8-1
	SIRPG	NM_001039508.2		c.748+919C>G		intron	N/A	NP_001034597.1	Q9P1W8-4
	SIRPG	NM_080816.3		c.431-4963C>G		intron	N/A	NP_543006.2	Q9P1W8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRPG	ENST00000303415.7	TSL:1 MANE Select	c.1079C>G	p.Pro360Arg	missense splice_region	Exon 4 of 6	ENSP00000305529.3	Q9P1W8-1
	SIRPG	ENST00000381580.5	TSL:1	c.980C>G	p.Pro327Arg	missense splice_region	Exon 4 of 6	ENSP00000370992.1	Q9P1W8-2
	SIRPG	ENST00000216927.4	TSL:1	c.748+919C>G		intron	N/A	ENSP00000216927.4	Q9P1W8-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000407 AC: 1 AN: 245696 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448310 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 718268

African (AFR) AF: 0.00 AC: 0 AN: 33032

American (AMR) AF: 0.0000231 AC: 1 AN: 43376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25584

East Asian (EAS) AF: 0.00 AC: 0 AN: 39388

South Asian (SAS) AF: 0.00 AC: 0 AN: 85726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102588

Other (OTH) AF: 0.00 AC: 0 AN: 59678

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.055
DANN	Benign	0.55
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0062	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.00071	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		-1.9
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.022
Sift	Benign	0.51	T
Sift4G	Benign	0.58	T
Polyphen		0.13	B
Vest4		0.094
MutPred		0.17		Loss of glycosylation at P360 (P = 0.0383)
MVP		0.18
MPC		0.023
ClinPred		0.050	T
GERP RS		-3.2
Varity_R		0.026
gMVP		0.55
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00094
dbscSNV1_RF	Benign	0.20
SpliceAI score (max)		0.070		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: rs547634798; hg19: chr20-1615915;