Genetic Variant NM_032813.5:c.1751G>T (chr13-100625620-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_032813.5(TMTC4):c.1751G>T(p.Arg584Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R584W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMTC4
NM_032813.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.35

Publications

2 publications found

Variant links:

Genes affected

TMTC4 (HGNC:25904): (transmembrane O-mannosyltransferase targeting cadherins 4) This gene encodes a transmembrane protein that belongs to family of proteins containing an N-terminal transmembrane domain and a C-terminal tetratricopeptide repeat (TPR) domain. TPR domains mediate protein-protein interactions in various cellular processes, such as synaptic vesicle fusion, protein folding, and protein translocation. A pseudogene of this gene has been defined on chromosome 5. [provided by RefSeq, Apr 2017]

TMTC4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.822

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032813.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMTC4	NM_032813.5	MANE Select	c.1751G>T	p.Arg584Leu	missense	Exon 15 of 19	NP_116202.2	Q5T4D3-3
TMTC4	NM_001350571.2		c.1925G>T	p.Arg642Leu	missense	Exon 16 of 20	NP_001337500.1
TMTC4	NM_001350574.2		c.1868G>T	p.Arg623Leu	missense	Exon 15 of 19	NP_001337503.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMTC4	ENST00000342624.10	TSL:2 MANE Select	c.1751G>T	p.Arg584Leu	missense	Exon 15 of 19	ENSP00000343871.5	Q5T4D3-3
TMTC4	ENST00000376234.7	TSL:1	c.1694G>T	p.Arg565Leu	missense	Exon 14 of 18	ENSP00000365408.3	Q5T4D3-1
TMTC4	ENST00000462211.5	TSL:1	n.1111G>T		non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251480

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Benign

0.073

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.038

MetaRNN

Pathogenic

0.82

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.5

PhyloP100

3.3

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.24

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.031

Polyphen

0.026

Vest4

0.69

MutPred

0.74

Loss of disorder (P = 0.0405)

MVP

0.64

MPC

0.13

ClinPred

0.97

GERP RS

3.7

Varity_R

0.31

gMVP

0.75

Mutation Taster

=64/36

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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