3-129670520-C-G

Variant names:

• chr3-129670520-C-G
• rs148011506
• NM_001017395.5:c.1321G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001017395.5(TMCC1):​c.1321G>C​(p.Ala441Pro) 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. 15/22 in silico tools predict 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. A441T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMCC1 NM_001017395.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1829234).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017395.5. 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
	TMCC1	NM_001017395.5	MANE Select	c.1321G>C	p.Ala441Pro	missense	Exon 5 of 7	NP_001017395.2	O94876-1
	TMCC1	NM_001349263.2		c.1321G>C	p.Ala441Pro	missense	Exon 6 of 8	NP_001336192.1	O94876-1
	TMCC1	NM_001349264.2		c.1321G>C	p.Ala441Pro	missense	Exon 5 of 7	NP_001336193.1	O94876-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCC1	ENST00000393238.8	TSL:1 MANE Select	c.1321G>C	p.Ala441Pro	missense	Exon 5 of 7	ENSP00000376930.3	O94876-1
	TMCC1	ENST00000432054.6	TSL:1	c.349G>C	p.Ala117Pro	missense	Exon 2 of 4	ENSP00000404711.2	Q6N039
	TMCC1	ENST00000858270.1		c.1321G>C	p.Ala441Pro	missense	Exon 6 of 8	ENSP00000528329.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.93	N
PhyloP100		1.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.11
Sift	Benign	0.50	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.096
MutPred		0.75		Loss of sheet (P = 0.1398)
MVP		0.25
MPC		1.1
ClinPred		0.17	T
GERP RS		4.4
Varity_R		0.13
gMVP		0.26
Mutation Taster		=75/25	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: rs148011506; hg19: chr3-129389363;