12-94581668-T-C

Position:

• chr12-94581668-T-C

Variant summary

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

The NM_020698.4(TMCC3):​c.949A>G​(p.Arg317Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMCC3 NM_020698.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMCC3	NM_020698.4	c.949A>G	p.Arg317Gly	missense_variant	2/4	ENST00000261226.9	NP_065749.3
TMCC3	NM_001301036.2	c.856A>G	p.Arg286Gly	missense_variant	2/4		NP_001287965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMCC3	ENST00000261226.9	c.949A>G	p.Arg317Gly	missense_variant	2/4	1	NM_020698.4	ENSP00000261226.4
TMCC3	ENST00000551457.1	c.856A>G	p.Arg286Gly	missense_variant	2/4	1		ENSP00000449888.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

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

Oct 07, 2024

The c.949A>G (p.R317G) alteration is located in exon 2 (coding exon 2) of the TMCC3 gene. This alteration results from a A to G substitution at nucleotide position 949, causing the arginine (R) at amino acid position 317 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	Benign	0.11
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Benign	0.25
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.036	D;D
Polyphen		0.0	B;.
Vest4		0.69
MutPred		0.65		Loss of helix (P = 0.0376);.;
MVP		0.061
MPC		0.35
ClinPred		0.53	D
GERP RS		2.0
Varity_R		0.67
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: chr12-94975444;