rs112049465

Variant names:

• chr13-100614376-C-A
• rs112049465
• NM_032813.5:c.1891G>T

Your query was ambiguous. Multiple possible variants found:

• chr13-100614376-C-A
• chr13-100614376-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_032813.5(TMTC4):​c.1891G>T​(p.Val631Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,870 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V631M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000034 (2 hom.)
• Consequence: TMTC4 NM_032813.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.499
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14787021).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMTC4	NM_032813.5	MANE Select	c.1891G>T	p.Val631Leu	missense	Exon 16 of 19	NP_116202.2	Q5T4D3-3
	TMTC4	NM_001350571.2		c.2065G>T	p.Val689Leu	missense	Exon 17 of 20	NP_001337500.1
	TMTC4	NM_001350574.2		c.2008G>T	p.Val670Leu	missense	Exon 16 of 19	NP_001337503.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMTC4	ENST00000342624.10	TSL:2 MANE Select	c.1891G>T	p.Val631Leu	missense	Exon 16 of 19	ENSP00000343871.5	Q5T4D3-3
	TMTC4	ENST00000376234.7	TSL:1	c.1834G>T	p.Val612Leu	missense	Exon 15 of 18	ENSP00000365408.3	Q5T4D3-1
	TMTC4	ENST00000861694.1		c.2065G>T	p.Val689Leu	missense	Exon 17 of 20	ENSP00000531753.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461870 Hom.: 2 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.67
DEOGEN2	Benign	0.0085	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.32	N
PhyloP100		0.50
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.052
Sift	Benign	0.81	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.37
MutPred		0.34		Gain of relative solvent accessibility (P = 0.1684)
MVP		0.30
MPC		0.095
ClinPred		0.33	T
GERP RS		3.5
Varity_R		0.053
gMVP		0.61
Mutation Taster		=94/5	polymorphism

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

Other links and lift over

dbSNP: rs112049465; hg19: chr13-101266630;