12-94581649-G-A

Position:

• chr12-94581649-G-A

Variant summary

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

The NM_020698.4(TMCC3):​c.968C>T​(p.Ser323Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000278 in 1,438,612 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TMCC3 NM_020698.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50

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.968C>T	p.Ser323Phe	missense_variant	2/4	ENST00000261226.9	NP_065749.3
TMCC3	NM_001301036.2	c.875C>T	p.Ser292Phe	missense_variant	2/4		NP_001287965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMCC3	ENST00000261226.9	c.968C>T	p.Ser323Phe	missense_variant	2/4	1	NM_020698.4	ENSP00000261226.4
TMCC3	ENST00000551457.1	c.875C>T	p.Ser292Phe	missense_variant	2/4	1		ENSP00000449888.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1438612 Hom.: 0 Cov.: 29 AF XY: 0.00000422 AC XY: 3 AN XY: 711504

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000474

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Aug 20, 2024

The c.968C>T (p.S323F) alteration is located in exon 2 (coding exon 2) of the TMCC3 gene. This alteration results from a C to T substitution at nucleotide position 968, causing the serine (S) at amino acid position 323 to be replaced by a phenylalanine (F). 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	0.43
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T;.
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.050	T;D
Polyphen		1.0	D;.
Vest4		0.74
MutPred		0.66		Loss of disorder (P = 0.0468);.;
MVP		0.23
MPC		1.0
ClinPred		0.92	D
GERP RS		5.9
Varity_R		0.53
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs776843349; hg19: chr12-94975425;