chr12-50925447-T-C

Position:

• chr12-50925447-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014033.4(TMT1A):​c.409T>C​(p.Ser137Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 31)
• Consequence: TMT1A NM_014033.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80

Genes affected

TMT1A (HGNC:24550): (thiol methyltransferase 1A) Predicted to enable methyltransferase activity. Predicted to be involved in methylation. Located in lipid droplet. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMT1A	NM_014033.4	c.409T>C	p.Ser137Pro	missense_variant	1/2	ENST00000332160.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMT1A	ENST00000332160.5	c.409T>C	p.Ser137Pro	missense_variant	1/2	1	NM_014033.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

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

Dec 06, 2022

The c.409T>C (p.S137P) alteration is located in exon 1 (coding exon 1) of the METTL7A gene. This alteration results from a T to C substitution at nucleotide position 409, causing the serine (S) at amino acid position 137 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	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Uncertain	2.9	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.43	B;.;B
Vest4		0.74
MutPred		0.59		Gain of catalytic residue at V141 (P = 9e-04);Gain of catalytic residue at V141 (P = 9e-04);Gain of catalytic residue at V141 (P = 9e-04);
MVP		0.68
MPC		0.46
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.87
gMVP		0.84

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: rs1158523861; hg19: chr12-51319230;