NM_203349.4:c.957A>G

Variant names:

• chr15-48857805-T-C
• rs766590732
• NM_203349.4:c.957A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_203349.4(SHC4):​c.957A>G​(p.Ile319Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000503 in 1,392,768 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: SHC4 NM_203349.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.346
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203349.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHC4	NM_203349.4	MANE Select	c.957A>G	p.Ile319Met	missense	Exon 7 of 12	NP_976224.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHC4	ENST00000332408.9	TSL:1 MANE Select	c.957A>G	p.Ile319Met	missense	Exon 7 of 12	ENSP00000329668.4	Q6S5L8-1
	SHC4	ENST00000396535.7	TSL:1	c.228A>G	p.Ile76Met	missense	Exon 4 of 9	ENSP00000379786.3	Q6S5L8-2
	SHC4	ENST00000537958.5	TSL:2	c.99A>G	p.Ile33Met	missense	Exon 5 of 10	ENSP00000443300.1	F5H5M1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000448 AC: 1 AN: 223090 AF XY: 0.00000825

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000955

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000503 AC: 7 AN: 1392768 Hom.: 0 Cov.: 30 AF XY: 0.00000724 AC XY: 5 AN XY: 690786

African (AFR) AF: 0.00 AC: 0 AN: 31614

American (AMR) AF: 0.00 AC: 0 AN: 38004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24274

East Asian (EAS) AF: 0.00 AC: 0 AN: 38130

South Asian (SAS) AF: 0.00 AC: 0 AN: 70488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5492

European-Non Finnish (NFE) AF: 0.00000650 AC: 7 AN: 1077122

Other (OTH) AF: 0.00 AC: 0 AN: 57074

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.083
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.29	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		0.35
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.69		Gain of sheet (P = 0.1208)
MVP		0.50
MPC		0.62
ClinPred		0.97	D
GERP RS		0.20
Varity_R		0.73
gMVP		0.61

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

Other links and lift over

dbSNP: rs766590732; hg19: chr15-49150002;