15-48851194-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_203349.4(SHC4):c.1297G>A(p.Ala433Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,670 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: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SHC4 NM_203349.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.126

Genes affected

SHC4 (HGNC:16743): (SHC adaptor protein 4) Predicted to enable receptor tyrosine kinase binding activity. Predicted to be involved in transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to act upstream of or within several processes, including apoptotic process; positive regulation of cell population proliferation; and stem cell differentiation. Predicted to be located in postsynaptic membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031380296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHC4	NM_203349.4	c.1297G>A	p.Ala433Thr	missense_variant	9/12	ENST00000332408.9
SHC4	XM_005254375.4	c.748G>A	p.Ala250Thr	missense_variant	9/12
SHC4	XM_047432492.1	c.439G>A	p.Ala147Thr	missense_variant	6/9
SHC4	XM_047432493.1	c.439G>A	p.Ala147Thr	missense_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHC4	ENST00000332408.9	c.1297G>A	p.Ala433Thr	missense_variant	9/12	1	NM_203349.4	P1
SHC4	ENST00000396535.7	c.568G>A	p.Ala190Thr	missense_variant	6/9	1
SHC4	ENST00000537958.5	c.439G>A	p.Ala147Thr	missense_variant	7/10	2
SHC4	ENST00000557797.5	c.384+4759G>A		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461670 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727112

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.1297G>A (p.A433T) alteration is located in exon 9 (coding exon 9) of the SHC4 gene. This alteration results from a G to A substitution at nucleotide position 1297, causing the alanine (A) at amino acid position 433 to be replaced by a threonine (T). 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	0.067
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	4.9
Dann	Benign	0.52
DEOGEN2	Benign	0.048	T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.031	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.35	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.23	N;N;N
REVEL	Benign	0.019
Sift	Benign	0.60	T;T;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.14
MutPred		0.29		Gain of disorder (P = 0.0876);.;.;
MVP		0.11
MPC		0.13
ClinPred		0.046	T
GERP RS		0.65
Varity_R		0.037
gMVP		0.31

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: rs372837256; hg19: chr15-49143391;