chr20-1635284-C-T

Variant names:

• chr20-1635284-C-T
• rs778222328
• NM_018556.4:c.1064G>A

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.1064G>A​(p.Ser355Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000422 in 1,611,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: SIRPG NM_018556.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.752
• 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=0.06595728).

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.1064G>A	p.Ser355Asn	missense	Exon 4 of 6	NP_061026.2	Q9P1W8-1
	SIRPG	NM_001039508.2		c.748+904G>A		intron	N/A	NP_001034597.1	Q9P1W8-4
	SIRPG	NM_080816.3		c.431-4978G>A		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.1064G>A	p.Ser355Asn	missense	Exon 4 of 6	ENSP00000305529.3	Q9P1W8-1
	SIRPG	ENST00000381580.5	TSL:1	c.965G>A	p.Ser322Asn	missense	Exon 4 of 6	ENSP00000370992.1	Q9P1W8-2
	SIRPG	ENST00000216927.4	TSL:1	c.748+904G>A		intron	N/A	ENSP00000216927.4	Q9P1W8-4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249980 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000432 AC: 63 AN: 1459588 Hom.: 0 Cov.: 29 AF XY: 0.0000413 AC XY: 30 AN XY: 725654

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.0000672 AC: 3 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000468 AC: 52 AN: 1110136

Other (OTH) AF: 0.000133 AC: 8 AN: 60280

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74332

African (AFR) AF: 0.0000483 AC: 2 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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	0.074
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.42
DANN	Benign	0.61
DEOGEN2	Benign	0.0082	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.75
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.0050
Sift	Benign	0.16	T
Sift4G	Benign	0.23	T
Polyphen		0.046	B
Vest4		0.085
MutPred		0.23		Loss of phosphorylation at S355 (P = 0.0523)
MVP		0.20
MPC		0.022
ClinPred		0.045	T
GERP RS		-0.048
Varity_R		0.037
gMVP		0.33
Mutation Taster		=96/4	polymorphism

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: rs778222328; hg19: chr20-1615930;