20-1635269-G-A

Variant names:

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

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>T​(p.Pro360Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000621 in 1,448,308 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P360R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SIRPG NM_018556.4 missense, splice_region
• Scores: Splicing: ADA: 0.001044
• Clinical Significance: Not reported in ClinVar
• 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=0.043952048).

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>T	p.Pro360Leu	missense splice_region	Exon 4 of 6	NP_061026.2	Q9P1W8-1
	SIRPG	NM_001039508.2		c.748+919C>T		intron	N/A	NP_001034597.1	Q9P1W8-4
	SIRPG	NM_080816.3		c.431-4963C>T		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>T	p.Pro360Leu	missense splice_region	Exon 4 of 6	ENSP00000305529.3	Q9P1W8-1
	SIRPG	ENST00000381580.5	TSL:1	c.980C>T	p.Pro327Leu	missense splice_region	Exon 4 of 6	ENSP00000370992.1	Q9P1W8-2
	SIRPG	ENST00000216927.4	TSL:1	c.748+919C>T		intron	N/A	ENSP00000216927.4	Q9P1W8-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000621 AC: 9 AN: 1448308 Hom.: 0 Cov.: 29 AF XY: 0.00000418 AC XY: 3 AN XY: 718268

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

American (AMR) AF: 0.00 AC: 0 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: 0.00000816 AC: 9 AN: 1102586

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.051
DANN	Benign	0.73
DEOGEN2	Benign	0.0078	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.00056	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L
PhyloP100		-1.9
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.0060
Sift	Benign	0.70	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.054
MutPred		0.23		Loss of glycosylation at P360 (P = 0.0383)
MVP		0.16
MPC		0.022
ClinPred		0.056	T
GERP RS		-3.2
Varity_R		0.018
gMVP		0.50
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0010
dbscSNV1_RF	Benign	0.17
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: rs547634798; hg19: chr20-1615915;