Genetic Variant SHC3:p.Thr552Arg (chr9-89037994-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016848.6(SHC3):c.1655C>G(p.Thr552Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000688 in 1,454,072 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SHC3
NM_016848.6 missense, splice_region

Scores

Splicing: ADA: 0.9784

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.79

Variant links:

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]

SHC3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHC3	NM_016848.6 link	c.1655C>G	p.Thr552Arg	missense_variant, splice_region_variant	Exon 11 of 12	ENST00000375835.9	NP_058544.3	Q92529-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHC3	ENST00000375835.9 link	c.1655C>G	p.Thr552Arg	missense_variant, splice_region_variant	Exon 11 of 12	1	NM_016848.6	ENSP00000364995.4		Q92529-1
SHC3	ENST00000375831.1 link	c.299C>G	p.Thr100Arg	missense_variant, splice_region_variant	Exon 2 of 3	2		ENSP00000364991.1		Q5T7I8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000407

AC:

AN:

245864

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133364

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454072

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723546

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1655C>G (p.T552R) alteration is located in exon 11 (coding exon 11) of the SHC3 gene. This alteration results from a C to G substitution at nucleotide position 1655, causing the threonine (T) at amino acid position 552 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

D;T

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

D;T

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

-1.1

N;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-2.1

N;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.021

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

1.0

D;.

Vest4

0.68

MutPred

0.45

Loss of methylation at K556 (P = 0.0602);.;

MVP

0.90

MPC

0.85

ClinPred

0.79

GERP RS

4.1

Varity_R

0.46

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.75

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over