rs1057517698

Variant names:

• chr12-88148318-G-A
• rs1057517698
• NM_181783.4:c.3G>A
• TMTC3 p.Met1?

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate 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
• Publications: 1 publications found

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: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 61 codons. Genomic position: 88148496. Lost 0.066 part of the original CDS.
• 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 VariationId is 372277.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMTC3	NM_181783.4	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 2 of 14	NP_861448.2	Q6ZXV5-2
	TMTC3	NM_001366579.1		c.3G>A	p.Met1?	start_lost	Exon 2 of 13	NP_001353508.1
	TMTC3	NM_001366574.1		c.-77-101G>A		intron	N/A	NP_001353503.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMTC3	ENST00000266712.11	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 2 of 14	ENSP00000266712.6	Q6ZXV5-2
	TMTC3	ENST00000547034.5	TSL:1	n.3G>A		non_coding_transcript_exon	Exon 2 of 12	ENSP00000448733.1	F8VRY4
	TMTC3	ENST00000869786.1		c.3G>A	p.Met1?	start_lost	Exon 2 of 14	ENSP00000539845.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Lissencephaly 8 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.70	T
PhyloP100		8.7
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.045	D
gMVP		0.75
Mutation Taster		=14/186	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1057517698;

hg19: chr12-88542095;