9-89038160-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_016848.6(SHC3):c.1489G>A(p.Glu497Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00307 in 1,614,028 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (16 hom.)
• Consequence: SHC3 NM_016848.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.00

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009997219).
• BP6: Variant 9-89038160-C-T is Benign according to our data. Variant chr9-89038160-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 710663.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 332 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHC3	NM_016848.6	c.1489G>A	p.Glu497Lys	missense_variant	11/12	ENST00000375835.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHC3	ENST00000375835.9	c.1489G>A	p.Glu497Lys	missense_variant	11/12	1	NM_016848.6	P1
SHC3	ENST00000375831.1	c.133G>A	p.Glu45Lys	missense_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00340

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00362

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00298 AC: 749 AN: 251486 Hom.: 1 AF XY: 0.00337 AC XY: 458 AN XY: 135914

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00559

Gnomad FIN exome AF: 0.00351

Gnomad NFE exome AF: 0.00408

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00316 AC: 4621 AN: 1461890 Hom.: 16 Cov.: 33 AF XY: 0.00330 AC XY: 2401 AN XY: 727246

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00601

Gnomad4 FIN exome AF: 0.00337

Gnomad4 NFE exome AF: 0.00335

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00218 AC: 332 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.00225 AC XY: 167 AN XY: 74380

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00333

Gnomad4 FIN AF: 0.00340

Gnomad4 NFE AF: 0.00362

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00290 Hom.: 1

Bravo AF: 0.00186

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00345 AC: 419

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00338

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;T
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.091
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;T
Sift4G	Uncertain	0.046	D;D
Polyphen		0.93	P;.
Vest4		0.30
MVP		0.72
MPC		0.62
ClinPred		0.072	T
GERP RS		3.3
Varity_R		0.34
gMVP		0.65

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

LitVar

Other links and lift over

dbSNP: rs149700558; hg19: chr9-91653075; COSMIC: COSV105312576;