chr9-89038274-C-A

Variant names:

• chr9-89038274-C-A
• NM_016848.6:c.1375G>T

Variant summary

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

The NM_016848.6(SHC3):​c.1375G>T​(p.Ala459Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SHC3 NM_016848.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.67
• Publications: 0 publications found

Genes affected

SHC3 (HGNC:18181): (SHC adaptor protein 3) Enables phosphotyrosine residue binding activity. Predicted to be involved in transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to act upstream of or within glutamatergic synaptic transmission and learning or memory. Predicted to be located in cytosol. Predicted to be active in plasma membrane. [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_016848.6. 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
	SHC3	NM_016848.6	MANE Select	c.1375G>T	p.Ala459Ser	missense	Exon 11 of 12	NP_058544.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHC3	ENST00000375835.9	TSL:1 MANE Select	c.1375G>T	p.Ala459Ser	missense	Exon 11 of 12	ENSP00000364995.4	Q92529-1
	SHC3	ENST00000375831.1	TSL:2	c.19G>T	p.Ala7Ser	missense	Exon 2 of 3	ENSP00000364991.1	Q5T7I8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

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	0.15
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.17
Sift	Benign	0.031	D
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.69
MutPred		0.20		Gain of phosphorylation at A459 (P = 0.0723)
MVP		0.75
MPC		0.43
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.21
gMVP		0.36
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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

hg19: chr9-91653189;