12-94581824-C-T

Variant names:

• chr12-94581824-C-T
• rs759024284
• NM_020698.4:c.793G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020698.4(TMCC3):​c.793G>A​(p.Ala265Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,650 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. A265S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMCC3 NM_020698.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33743674).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020698.4. 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
	TMCC3	NM_020698.4	MANE Select	c.793G>A	p.Ala265Thr	missense	Exon 2 of 4	NP_065749.3	Q9ULS5
	TMCC3	NM_001301036.2		c.700G>A	p.Ala234Thr	missense	Exon 2 of 4	NP_001287965.1	G3V207

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCC3	ENST00000261226.9	TSL:1 MANE Select	c.793G>A	p.Ala265Thr	missense	Exon 2 of 4	ENSP00000261226.4	Q9ULS5
	TMCC3	ENST00000551457.1	TSL:1	c.700G>A	p.Ala234Thr	missense	Exon 2 of 4	ENSP00000449888.1	G3V207
	TMCC3	ENST00000896389.1		c.793G>A	p.Ala265Thr	missense	Exon 2 of 5	ENSP00000566448.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461650 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727074

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111832

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.0032	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.049	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.22
Sift	Uncertain	0.018	D
Sift4G	Benign	0.14	T
Polyphen		0.94	P
Vest4		0.34
MutPred		0.51		Gain of glycosylation at A265 (P = 0.0069)
MVP		0.13
MPC		0.51
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.22
gMVP		0.38
Mutation Taster		=52/48	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: rs759024284; hg19: chr12-94975600; COSMIC: COSV54151852; COSMIC: COSV54151852;