chr1-20721994-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001103161.2(SH2D5):​c.1070A>G​(p.His357Arg) 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. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SH2D5 NM_001103161.2 missense, splice_region
• Scores: Splicing: ADA: 0.0003086
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20839375).

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>G	p.His357Arg	missense splice_region	Exon 10 of 10	NP_001096631.1	Q6ZV89-1
	SH2D5	NM_001103160.2		c.818A>G	p.His273Arg	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>G	p.His357Arg	missense splice_region	Exon 10 of 10	ENSP00000406026.2	Q6ZV89-1
	SH2D5	ENST00000870131.1		c.1070A>G	p.His357Arg	missense splice_region	Exon 11 of 11	ENSP00000540190.1
	SH2D5	ENST00000870132.1		c.1070A>G	p.His357Arg	missense splice_region	Exon 11 of 11	ENSP00000540191.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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	Uncertain	0.37
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.074
Sift	Benign	0.30	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.59		Loss of sheet (P = 0.0817)
MVP		0.73
MPC		0.13
ClinPred		0.35	T
GERP RS		4.1
Varity_R		0.12
gMVP		0.43
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00031
dbscSNV1_RF	Benign	0.012
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: rs1570500553; hg19: chr1-21048487;