9-89013473-G-T

Variant names:

• chr9-89013473-G-T
• rs918214836
• NM_016848.6:c.1759C>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_016848.6(SHC3):​c.1759C>A​(p.Gln587Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,461,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: SHC3 NM_016848.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09647307).
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHC3	NM_016848.6	c.1759C>A	p.Gln587Lys	missense_variant	Exon 12 of 12	ENST00000375835.9	NP_058544.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHC3	ENST00000375835.9	c.1759C>A	p.Gln587Lys	missense_variant	Exon 12 of 12	1	NM_016848.6	ENSP00000364995.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461392 Hom.: 0 Cov.: 29 AF XY: 0.0000179 AC XY: 13 AN XY: 727032

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1759C>A (p.Q587K) alteration is located in exon 12 (coding exon 12) of the SHC3 gene. This alteration results from a C to A substitution at nucleotide position 1759, causing the glutamine (Q) at amino acid position 587 to be replaced by a lysine (K). 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	0.076
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Benign	0.79
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.038
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.92	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.058
Sift	Benign	0.79	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.090
MVP		0.64
MPC		0.27
ClinPred		0.21	T
GERP RS		5.3
Varity_R		0.20
gMVP		0.53

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: rs918214836; hg19: chr9-91628388;