chr4-8227070-G-C

Variant names:

• chr4-8227070-G-C
• NM_018986.5:c.1376G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018986.5(SH3TC1):​c.1376G>C​(p.Cys459Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SH3TC1 NM_018986.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.932
• Publications: 0 publications found

Genes affected

SH3TC1 (HGNC:26009): (SH3 domain and tetratricopeptide repeats 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054581344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3TC1	NM_018986.5	c.1376G>C	p.Cys459Ser	missense_variant	Exon 12 of 18	ENST00000245105.8	NP_061859.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3TC1	ENST00000245105.8	c.1376G>C	p.Cys459Ser	missense_variant	Exon 12 of 18	2	NM_018986.5	ENSP00000245105.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 70

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1376G>C (p.C459S) alteration is located in exon 12 (coding exon 11) of the SH3TC1 gene. This alteration results from a G to C substitution at nucleotide position 1376, causing the cysteine (C) at amino acid position 459 to be replaced by a serine (S). 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	0.13
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.29
DANN	Benign	0.43
DEOGEN2	Benign	0.000031	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-0.93
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.084
Sift	Benign	0.46	T
Sift4G	Benign	0.66	T
Polyphen		0.0030	B
Vest4		0.15
MutPred		0.17		Loss of catalytic residue at C459 (P = 0.0357);
MVP		0.26
MPC		0.035
ClinPred		0.031	T
GERP RS		1.6
Varity_R		0.041
gMVP		0.11
Mutation Taster		=99/1	polymorphism

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

hg19: chr4-8228797;