1-20721994-T-G

Variant names:

• chr1-20721994-T-G
• rs1570500553
• NM_001103161.2:c.1070A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001103161.2(SH2D5):​c.1070A>C​(p.His357Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/24 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. H357R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SH2D5 NM_001103161.2 missense, splice_region
• Scores: Splicing: ADA: 0.004655
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23
• Publications: 0 publications found

Genes affected

SH2D5 (HGNC:28819): (SH2 domain containing 5) Predicted to be active in postsynaptic density. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001103161.2. 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
	SH2D5	NM_001103161.2	MANE Select	c.1070A>C	p.His357Pro	missense splice_region	Exon 10 of 10	NP_001096631.1	Q6ZV89-1
	SH2D5	NM_001103160.2		c.818A>C	p.His273Pro	missense splice_region	Exon 9 of 9	NP_001096630.1	Q6ZV89-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D5	ENST00000444387.7	TSL:2 MANE Select	c.1070A>C	p.His357Pro	missense splice_region	Exon 10 of 10	ENSP00000406026.2	Q6ZV89-1
	SH2D5	ENST00000870131.1		c.1070A>C	p.His357Pro	missense splice_region	Exon 11 of 11	ENSP00000540190.1
	SH2D5	ENST00000870132.1		c.1070A>C	p.His357Pro	missense splice_region	Exon 11 of 11	ENSP00000540191.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.052	T
Eigen	Benign	0.034
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.22
Sift	Benign	0.039	D
Sift4G	Benign	0.068	T
Polyphen		0.51	P
Vest4		0.51
MutPred		0.59		Gain of glycosylation at H357 (P = 0.0547)
MVP		0.79
MPC		0.49
ClinPred		0.80	D
GERP RS		4.1
Varity_R		0.25
gMVP		0.73
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0047
dbscSNV1_RF	Benign	0.092
SpliceAI score (max)		0.010		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: rs1570500553; hg19: chr1-21048487;