rs1057517698

Positions:

• chr12-88148318-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_181783.4(TMTC3):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMTC3 NM_181783.4 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.69

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-88148318-G-A is Pathogenic according to our data. Variant chr12-88148318-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 372277.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMTC3	NM_181783.4	c.3G>A	p.Met1?	start_lost	2/14	ENST00000266712.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMTC3	ENST00000266712.11	c.3G>A	p.Met1?	start_lost	2/14	1	NM_181783.4	P1
TMTC3	ENST00000547034.5	c.3G>A	p.Met1?	start_lost, NMD_transcript_variant	2/12	1
TMTC3	ENST00000549011.5	c.3G>A	p.Met1?	start_lost	2/4	4
TMTC3	ENST00000551088.1	c.3G>A	p.Met1?	start_lost	2/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lissencephaly 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 17, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-1.4	N;N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.016	D;D;D
Sift4G	Uncertain	0.045	D;D;D
Polyphen		0.42	.;B;.
Vest4		0.96
MutPred		0.97		Gain of catalytic residue at L6 (P = 0.0017);Gain of catalytic residue at L6 (P = 0.0017);Gain of catalytic residue at L6 (P = 0.0017);
MVP		0.73
ClinPred		0.99	D
GERP RS		5.3
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.32		Position offset: -30

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057517698; hg19: chr12-88542095;