NM_018986.5:c.365G>C

Variant names:

• chr4-8212818-G-C
• rs200305611
• NM_018986.5:c.365G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018986.5(SH3TC1):​c.365G>C​(p.Arg122Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,431,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R122C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SH3TC1 NM_018986.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.275
• Publications: 5 publications found

Genes affected

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1919666).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018986.5. 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
	SH3TC1	NM_018986.5	MANE Select	c.365G>C	p.Arg122Pro	missense	Exon 4 of 18	NP_061859.4
	SH3TC1	NM_001410712.1		c.365G>C	p.Arg122Pro	missense	Exon 4 of 18	NP_001397641.1	A0A804HI81
	SH3TC1	NM_001318480.2		c.137G>C	p.Arg46Pro	missense	Exon 4 of 18	NP_001305409.2	H0YA34

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3TC1	ENST00000245105.8	TSL:2 MANE Select	c.365G>C	p.Arg122Pro	missense	Exon 4 of 18	ENSP00000245105.3	Q8TE82
	SH3TC1	ENST00000502669.5	TSL:1	n.290G>C		non_coding_transcript_exon	Exon 3 of 15	ENSP00000425970.1	D6RI07
	SH3TC1	ENST00000457650.7	TSL:5	c.365G>C	p.Arg122Pro	missense	Exon 5 of 19	ENSP00000390311.3	Q8TE82

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1431566 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 709440

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33042

American (AMR) AF: 0.00 AC: 0 AN: 40522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25232

East Asian (EAS) AF: 0.00 AC: 0 AN: 38524

South Asian (SAS) AF: 0.00 AC: 0 AN: 82008

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5130

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097150

Other (OTH) AF: 0.0000169 AC: 1 AN: 59092

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.28
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.38
Sift	Benign	0.28	T
Sift4G	Benign	0.32	T
Polyphen		0.87	P
Vest4		0.58
MutPred		0.36		Gain of glycosylation at S117 (P = 0.0103)
MVP		0.70
MPC		0.22
ClinPred		0.32	T
GERP RS		1.3
Varity_R		0.35
gMVP		0.60
Mutation Taster		=92/8	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

dbSNP: rs200305611; hg19: chr4-8214545;