NM_005490.3:c.1559A>C

Variant names:

• chr19-6753467-T-G
• rs1568260899
• NM_005490.3:c.1559A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005490.3(SH2D3A):​c.1559A>C​(p.Gln520Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000528 in 1,513,956 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: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SH2D3A NM_005490.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.46
• Publications: 0 publications found

Genes affected

SH2D3A (HGNC:16885): (SH2 domain containing 3A) Predicted to enable guanyl-nucleotide exchange factor activity and phosphotyrosine residue binding activity. Predicted to be involved in positive regulation of peptidyl-serine phosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0730696).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005490.3. 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
	SH2D3A	NM_005490.3	MANE Select	c.1559A>C	p.Gln520Pro	missense	Exon 9 of 10	NP_005481.2	Q9BRG2-1
	SH2D3A	NM_001439225.1		c.1646A>C	p.Gln549Pro	missense	Exon 8 of 9	NP_001426154.1
	SH2D3A	NM_001386585.1		c.1556A>C	p.Gln519Pro	missense	Exon 9 of 10	NP_001373514.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D3A	ENST00000245908.11	TSL:1 MANE Select	c.1559A>C	p.Gln520Pro	missense	Exon 9 of 10	ENSP00000245908.5	Q9BRG2-1
	SH2D3A	ENST00000892014.1		c.1646A>C	p.Gln549Pro	missense	Exon 8 of 9	ENSP00000562073.1
	SH2D3A	ENST00000892016.1		c.1643A>C	p.Gln548Pro	missense	Exon 8 of 9	ENSP00000562075.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000220 AC: 3 AN: 1361794 Hom.: 0 Cov.: 33 AF XY: 0.00000300 AC XY: 2 AN XY: 667202

African (AFR) AF: 0.00 AC: 0 AN: 30698

American (AMR) AF: 0.0000316 AC: 1 AN: 31682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23242

East Asian (EAS) AF: 0.00 AC: 0 AN: 34814

South Asian (SAS) AF: 0.00 AC: 0 AN: 75822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5542

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1056920

Other (OTH) AF: 0.0000356 AC: 2 AN: 56146

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.000327 AC: 5 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

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	0.18
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.71
DEOGEN2	Benign	0.0085	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		-1.5
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.067
Sift	Benign	0.28	T
Sift4G	Benign	0.26	T
Polyphen		0.26	B
Vest4		0.21
MutPred		0.44		Gain of methylation at R523 (P = 0.0505)
MVP		0.31
MPC		1.7
ClinPred		0.31	T
GERP RS		-2.2
Varity_R		0.32
gMVP		0.60
Mutation Taster		=89/11	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: rs1568260899; hg19: chr19-6753478;