13-100626091-T-G

Variant names:

• chr13-100626091-T-G
• NM_032813.5:c.1566A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032813.5(TMTC4):​c.1566A>C​(p.Arg522Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 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. R522I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMTC4 NM_032813.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0540
• 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: 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=0.107245).

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.1566A>C	p.Arg522Ser	missense	Exon 13 of 19	NP_116202.2	Q5T4D3-3
	TMTC4	NM_001350571.2		c.1740A>C	p.Arg580Ser	missense	Exon 14 of 20	NP_001337500.1
	TMTC4	NM_001350574.2		c.1683A>C	p.Arg561Ser	missense	Exon 13 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.1566A>C	p.Arg522Ser	missense	Exon 13 of 19	ENSP00000343871.5	Q5T4D3-3
	TMTC4	ENST00000376234.7	TSL:1	c.1509A>C	p.Arg503Ser	missense	Exon 12 of 18	ENSP00000365408.3	Q5T4D3-1
	TMTC4	ENST00000462211.5	TSL:1	n.926A>C		non_coding_transcript_exon	Exon 7 of 9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.0086	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.13	N
PhyloP100		0.054
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.062
Sift	Benign	0.73	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.47
MutPred		0.53		Loss of MoRF binding (P = 0.0078)
MVP		0.45
MPC		0.11
ClinPred		0.69	D
GERP RS		1.6
Varity_R		0.11
gMVP		0.45
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr13-101278345;