20-1635431-C-T

Position:

• chr20-1635431-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018556.4(SIRPG):​c.917G>A​(p.Gly306Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIRPG NM_018556.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.41

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRPG	NM_018556.4	c.917G>A	p.Gly306Asp	missense_variant	4/6	ENST00000303415.7
SIRPG-AS1	NR_110090.1	n.213+1711C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRPG	ENST00000303415.7	c.917G>A	p.Gly306Asp	missense_variant	4/6	1	NM_018556.4	P2
SIRPG-AS1	ENST00000456177.5	n.213+1711C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 72

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2023

The c.917G>A (p.G306D) alteration is located in exon 4 (coding exon 4) of the SIRPG gene. This alteration results from a G to A substitution at nucleotide position 917, causing the glycine (G) at amino acid position 306 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.058
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.0048	T
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-6.2	D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.49
MutPred		0.94		.;Loss of methylation at K304 (P = 0.1326);
MVP		0.68
MPC		0.20
ClinPred		1.0	D
GERP RS		1.6
Varity_R		0.93
gMVP		0.73

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-1616077;