chr12-94571632-T-C

Position:

• chr12-94571632-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000261226.9(TMCC3):​c.1237A>G​(p.Arg413Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMCC3 ENST00000261226.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.96

Genes affected

TMCC3 (HGNC:29199): (transmembrane and coiled-coil domain family 3) Enables 14-3-3 protein binding activity and identical protein binding activity. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35134947).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMCC3	NM_020698.4	c.1237A>G	p.Arg413Gly	missense_variant	4/4	ENST00000261226.9	NP_065749.3
TMCC3	NM_001301036.2	c.1144A>G	p.Arg382Gly	missense_variant	4/4		NP_001287965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMCC3	ENST00000261226.9	c.1237A>G	p.Arg413Gly	missense_variant	4/4	1	NM_020698.4	ENSP00000261226.4
TMCC3	ENST00000551457.1	c.1144A>G	p.Arg382Gly	missense_variant	4/4	1		ENSP00000449888.1

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

Apr 13, 2023

The c.1237A>G (p.R413G) alteration is located in exon 4 (coding exon 4) of the TMCC3 gene. This alteration results from a A to G substitution at nucleotide position 1237, causing the arginine (R) at amino acid position 413 to be replaced by a glycine (G). 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	Uncertain	0.46
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-0.026
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.97	L;.
MutationTaster	Benign	0.81	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.024	B;.
Vest4		0.22
MutPred		0.69		Loss of methylation at R413 (P = 0.0586);.;
MVP		0.10
MPC		0.37
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.68
gMVP		0.58

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: chr12-94965408;