3-129828117-C-G

Variant names:

• chr3-129828117-C-G
• rs764293379
• NM_001017395.5:c.262G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001017395.5(TMCC1):​c.262G>C​(p.Ala88Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMCC1 NM_001017395.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.64

Genes affected

TMCC1 (HGNC:29116): (transmembrane and coiled-coil domain family 1) Enables identical protein binding activity. Involved in several processes, including endosome fission; endosome membrane tubulation; and membrane fission. Located in cytosol; endoplasmic reticulum-endosome membrane contact site; and rough endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026501268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMCC1	NM_001017395.5	c.262G>C	p.Ala88Pro	missense_variant	Exon 4 of 7	ENST00000393238.8	NP_001017395.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMCC1	ENST00000393238.8	c.262G>C	p.Ala88Pro	missense_variant	Exon 4 of 7	1	NM_001017395.5	ENSP00000376930.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.262G>C (p.A88P) alteration is located in exon 3 (coding exon 1) of the TMCC1 gene. This alteration results from a G to C substitution at nucleotide position 262, causing the alanine (A) at amino acid position 88 to be replaced by a proline (P). 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	0.073
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.63
DANN	Benign	0.95
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.035
Sift	Benign	0.18	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.31		Gain of loop (P = 3e-04);
MVP		0.16
MPC		1.2
ClinPred		0.035	T
GERP RS		-5.7
Varity_R		0.045
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs764293379; hg19: chr3-129546960;