chr1-20722769-C-A

Variant names:

• chr1-20722769-C-A
• NM_001103161.2:c.1055G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001103161.2(SH2D5):​c.1055G>T​(p.Arg352Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000219 in 1,371,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. R352H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SH2D5 NM_001103161.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.03

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D5	NM_001103161.2	c.1055G>T	p.Arg352Leu	missense_variant	Exon 9 of 10	ENST00000444387.7	NP_001096631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2D5	ENST00000444387.7	c.1055G>T	p.Arg352Leu	missense_variant	Exon 9 of 10	2	NM_001103161.2	ENSP00000406026.2
SH2D5	ENST00000375031.5	c.803G>T	p.Arg268Leu	missense_variant	Exon 8 of 9	2		ENSP00000364171.1
SH2D5	ENST00000460804.5	n.786G>T		non_coding_transcript_exon_variant	Exon 5 of 6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1371034 Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1 AN XY: 674698

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000135

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000188

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.0093	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	.;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.9	.;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.046	D;D
Polyphen		0.63	.;P
Vest4		0.75
MutPred		0.60		.;Loss of methylation at R352 (P = 0.0188);
MVP		0.74
MPC		0.24
ClinPred		0.85	D
GERP RS		2.8
Varity_R		0.18
gMVP		0.63

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: chr1-21049262;