chr12-94581899-C-T

Variant names:

• chr12-94581899-C-T
• rs373520146
• NM_020698.4:c.718G>A

Variant summary

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

The NM_020698.4(TMCC3):​c.718G>A​(p.Gly240Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000762 in 1,614,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: TMCC3 NM_020698.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.102822036).

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.718G>A	p.Gly240Arg	missense	Exon 2 of 4	NP_065749.3	Q9ULS5
	TMCC3	NM_001301036.2		c.625G>A	p.Gly209Arg	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.718G>A	p.Gly240Arg	missense	Exon 2 of 4	ENSP00000261226.4	Q9ULS5
	TMCC3	ENST00000551457.1	TSL:1	c.625G>A	p.Gly209Arg	missense	Exon 2 of 4	ENSP00000449888.1	G3V207
	TMCC3	ENST00000896389.1		c.718G>A	p.Gly240Arg	missense	Exon 2 of 5	ENSP00000566448.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000127 AC: 32 AN: 251404 AF XY: 0.000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000793 AC: 116 AN: 1461892 Hom.: 0 Cov.: 29 AF XY: 0.0000921 AC XY: 67 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1112010

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74378

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.28
Sift	Benign	0.034	D
Sift4G	Uncertain	0.050	T
Polyphen		1.0	D
Vest4		0.46
MutPred		0.58		Gain of solvent accessibility (P = 0.0055)
MVP		0.13
MPC		1.0
ClinPred		0.21	T
GERP RS		5.9
Varity_R		0.31
gMVP		0.58
Mutation Taster		=73/27	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: rs373520146; hg19: chr12-94975675; COSMIC: COSV99705500; COSMIC: COSV99705500;