chr12-94571544-C-T

Variant names:

• chr12-94571544-C-T
• rs1184195180
• NM_020698.4:c.1325G>A

Variant summary

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

The NM_020698.4(TMCC3):​c.1325G>A​(p.Ser442Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TMCC3 NM_020698.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20

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]

MIR7844 (HGNC:50044): (microRNA 7844) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

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 rank	MANE	Protein	UniProt
TMCC3	NM_020698.4	c.1325G>A	p.Ser442Asn	missense_variant	Exon 4 of 4	ENST00000261226.9	NP_065749.3
TMCC3	NM_001301036.2	c.1232G>A	p.Ser411Asn	missense_variant	Exon 4 of 4		NP_001287965.1
MIR7844	NR_106998.1	n.-192G>A		upstream_gene_variant
MIR7844	unassigned_transcript_2046	n.-217G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMCC3	ENST00000261226.9	c.1325G>A	p.Ser442Asn	missense_variant	Exon 4 of 4	1	NM_020698.4	ENSP00000261226.4
TMCC3	ENST00000551457.1	c.1232G>A	p.Ser411Asn	missense_variant	Exon 4 of 4	1		ENSP00000449888.1
MIR7844	ENST00000616161.1	n.-192G>A		upstream_gene_variant		6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251428 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1325G>A (p.S442N) alteration is located in exon 4 (coding exon 4) of the TMCC3 gene. This alteration results from a G to A substitution at nucleotide position 1325, causing the serine (S) at amino acid position 442 to be replaced by an asparagine (N). 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	0.37
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.39
MutPred		0.80		Gain of relative solvent accessibility (P = 0.09);.;
MVP		0.18
MPC		0.28
ClinPred		0.83	D
GERP RS		5.3
Varity_R		0.65
gMVP		0.77

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: rs1184195180; hg19: chr12-94965320;