Genetic Variant TMTC3:p.Asn5Lys (chr12-88148330-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181783.4(TMTC3):c.15C>A(p.Asn5Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N5N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TMTC3
NM_181783.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.617

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

lissencephaly 8
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
periventricular nodular heterotopia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TMTC3 links:

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ACMG classification

Classification was made for transcript

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=0.21903309).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181783.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMTC3	NM_181783.4	MANE Select	c.15C>A	p.Asn5Lys	missense	Exon 2 of 14	NP_861448.2	Q6ZXV5-2
TMTC3	NM_001366579.1		c.15C>A	p.Asn5Lys	missense	Exon 2 of 13	NP_001353508.1
TMTC3	NM_001366574.1		c.-77-89C>A		intron	N/A	NP_001353503.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMTC3	ENST00000266712.11	TSL:1 MANE Select	c.15C>A	p.Asn5Lys	missense	Exon 2 of 14	ENSP00000266712.6	Q6ZXV5-2
TMTC3	ENST00000547034.5	TSL:1	n.15C>A		non_coding_transcript_exon	Exon 2 of 12	ENSP00000448733.1	F8VRY4
TMTC3	ENST00000869786.1		c.15C>A	p.Asn5Lys	missense	Exon 2 of 14	ENSP00000539845.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456932

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724476

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33244

American (AMR)

AF:

0.00

AC:

AN:

43962

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25938

East Asian (EAS)

AF:

0.00

AC:

AN:

39602

South Asian (SAS)

AF:

0.00

AC:

AN:

84800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5580

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110278

Other (OTH)

AF:

0.00

AC:

AN:

60174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.024

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.093

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.62

M_CAP

Benign

0.039

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.81

PhyloP100

0.62

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.3

REVEL

Benign

0.072

Sift

Uncertain

0.029

Sift4G

Benign

0.22

Polyphen

0.57

Vest4

0.17

MutPred

0.31

Gain of catalytic residue at I4 (P = 0.0215)

MVP

0.60

MPC

0.41

ClinPred

0.78

GERP RS

3.5

gMVP

0.40

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over