NM_001040023.2:c.353C>T

Variant names:

• chr20-1915372-C-T
• rs138711836
• NM_001040023.2:c.353C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_001040023.2(SIRPA):​c.353C>T​(p.Thr118Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000458 in 1,609,758 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00046 (1 hom.)
• Consequence: SIRPA NM_001040023.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.104
• Publications: 0 publications found

Genes affected

SIRPA (HGNC:9662): (signal regulatory protein alpha) 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. This protein can be phosphorylated by tyrosine kinases. The phospho-tyrosine residues of this PTP have been shown to recruit SH2 domain containing tyrosine phosphatases (PTP), and serve as substrates of PTPs. This protein was found to participate in signal transduction mediated by various growth factor receptors. CD47 has been demonstrated to be a ligand for this receptor protein. This gene and its product share very high similarity with several other members of the SIRP family. These related genes are located in close proximity to each other on chromosome 20p13. Multiple alternatively spliced transcript variants have been determined for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1403766).
• BP6: Variant 20-1915372-C-T is Benign according to our data. Variant chr20-1915372-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3025288.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040023.2. 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
	SIRPA	NM_001040023.2	MANE Select	c.353C>T	p.Thr118Ile	missense	Exon 2 of 8	NP_001035112.1	P78324-1
	SIRPA	NM_001330728.1		c.353C>T	p.Thr118Ile	missense	Exon 3 of 9	NP_001317657.1	P78324-2
	SIRPA	NM_001040022.1		c.353C>T	p.Thr118Ile	missense	Exon 3 of 9	NP_001035111.1	P78324-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRPA	ENST00000358771.5	TSL:1 MANE Select	c.353C>T	p.Thr118Ile	missense	Exon 2 of 8	ENSP00000351621.4	P78324-1
	SIRPA	ENST00000356025.7	TSL:1	c.353C>T	p.Thr118Ile	missense	Exon 3 of 9	ENSP00000348307.3	P78324-1
	SIRPA	ENST00000400068.7	TSL:1	c.353C>T	p.Thr118Ile	missense	Exon 3 of 9	ENSP00000382941.4	P78324-1

Frequencies

GnomAD3 genomes AF: 0.000451 AC: 67 AN: 148702 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000439

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000819

Gnomad OTH AF: 0.000979

GnomAD2 exomes AF: 0.000272 AC: 66 AN: 242960 AF XY: 0.000289

Gnomad AFR exome AF: 0.000189

Gnomad AMR exome AF: 0.000212

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000451

Gnomad OTH exome AF: 0.000338

GnomAD4 exome AF: 0.000459 AC: 670 AN: 1460936 Hom.: 1 Cov.: 62 AF XY: 0.000432 AC XY: 314 AN XY: 726808

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000120 AC: 4 AN: 33466

American (AMR) AF: 0.000335 AC: 15 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86228

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.000543 AC: 603 AN: 1111170

Other (OTH) AF: 0.000414 AC: 25 AN: 60366

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000450 AC: 67 AN: 148822 Hom.: 0 Cov.: 31 AF XY: 0.000428 AC XY: 31 AN XY: 72478

African (AFR) AF: 0.000147 AC: 6 AN: 40714

American (AMR) AF: 0.000136 AC: 2 AN: 14728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3428

East Asian (EAS) AF: 0.00 AC: 0 AN: 4748

South Asian (SAS) AF: 0.000440 AC: 2 AN: 4550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000819 AC: 55 AN: 67168

Other (OTH) AF: 0.000969 AC: 2 AN: 2064

Alfa AF: 0.000612 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000699 AC: 6

ExAC AF: 0.000486 AC: 59

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.10
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.20
Sift	Benign	0.094	T
Sift4G	Benign	0.12	T
Polyphen		0.14	B
Vest4		0.13
MVP		0.75
MPC		0.70
ClinPred		0.10	T
GERP RS		0.88
Varity_R		0.21
gMVP		0.61
Mutation Taster		=83/17	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: rs138711836; hg19: chr20-1896018;