chr15-48834946-C-A

Position:

• chr15-48834946-C-A

Variant summary

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

The NM_203349.4(SHC4):​c.1560G>T​(p.Gln520His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHC4 NM_203349.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.684

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 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/exons	MANE	UniProt
SHC4	NM_203349.4	c.1560G>T	p.Gln520His	missense_variant	11/12	ENST00000332408.9
SHC4	XM_005254375.4	c.1011G>T	p.Gln337His	missense_variant	11/12
SHC4	XM_047432492.1	c.702G>T	p.Gln234His	missense_variant	8/9
SHC4	XM_047432493.1	c.702G>T	p.Gln234His	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHC4	ENST00000332408.9	c.1560G>T	p.Gln520His	missense_variant	11/12	1	NM_203349.4	P1
SHC4	ENST00000396535.7	c.831G>T	p.Gln277His	missense_variant	8/9	1
SHC4	ENST00000537958.5	c.702G>T	p.Gln234His	missense_variant	9/10	2
SHC4	ENST00000557797.5	c.*206G>T		3_prime_UTR_variant, NMD_transcript_variant	7/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Mar 01, 2023

The c.1560G>T (p.Q520H) alteration is located in exon 11 (coding exon 11) of the SHC4 gene. This alteration results from a G to T substitution at nucleotide position 1560, causing the glutamine (Q) at amino acid position 520 to be replaced by a histidine (H). 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	0.21
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T;.;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.0	M;.;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.54
MutPred		0.40		Loss of catalytic residue at Q520 (P = 0.0503);.;.;
MVP		0.79
MPC		0.58
ClinPred		0.98	D
GERP RS		3.0
Varity_R		0.46
gMVP		0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-49127143;