Genetic Variant TMTC3:p.Asn54His (chr12-88148475-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_181783.4(TMTC3):c.160A>C(p.Asn54His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,188 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

TMTC3
NM_181783.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.29

Variant links:

Genes affected

TMTC3 (HGNC:26899): (transmembrane O-mannosyltransferase targeting cadherins 3) This gene encodes a protein that belongs to the transmembrane and tetratricopeptide repeat-containing protein family. [provided by RefSeq, May 2010]

TMTC3 links:

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ACMG classification

Classification made for transcript

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
TMTC3	NM_181783.4 link	c.160A>C	p.Asn54His	missense_variant	Exon 2 of 14	ENST00000266712.11	NP_861448.2	Q6ZXV5-2A8K321

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMTC3	ENST00000266712.11 link	c.160A>C	p.Asn54His	missense_variant	Exon 2 of 14	1	NM_181783.4	ENSP00000266712.6	Q6ZXV5-2
TMTC3	ENST00000547034.5 link	n.160A>C		non_coding_transcript_exon_variant	Exon 2 of 12	1		ENSP00000448733.1	F8VRY4
TMTC3	ENST00000549011.5 link	c.160A>C	p.Asn54His	missense_variant	Exon 2 of 4	4		ENSP00000447640.1	F8W044
TMTC3	ENST00000551088.1 link	c.160A>C	p.Asn54His	missense_variant	Exon 2 of 5	3		ENSP00000448566.1	F8VR71

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.160A>C (p.N54H) alteration is located in exon 2 (coding exon 1) of the TMTC3 gene. This alteration results from a A to C substitution at nucleotide position 160, causing the asparagine (N) at amino acid position 54 to be replaced by a histidine (H). 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

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.089

T;.;T

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Uncertain

0.77

MutationAssessor

Benign

1.7

.;L;.

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.5

D;D;D

REVEL

Pathogenic

0.70

Sift

Benign

0.10

T;D;T

Sift4G

Benign

0.27

T;T;T

Polyphen

1.0

.;D;.

Vest4

0.81

MutPred

0.69

Gain of catalytic residue at D55 (P = 5e-04);Gain of catalytic residue at D55 (P = 5e-04);Gain of catalytic residue at D55 (P = 5e-04);

MVP

0.90

MPC

1.1

ClinPred

0.99

GERP RS

5.4

gMVP

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over