rs754200057

Variant names:

• chr12-88153300-C-G
• rs754200057
• NM_181783.4:c.199C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-88153300-C-G
• chr12-88153300-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_181783.4(TMTC3):​c.199C>G​(p.His67Asp) variant causes a missense 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMTC3 NM_181783.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.55
• Publications: 4 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: G2P, Labcorp Genetics (formerly Invitae)
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896
• PP5: Variant 12-88153300-C-G is Pathogenic according to our data. Variant chr12-88153300-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 372276.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMTC3	NM_181783.4	MANE Select	c.199C>G	p.His67Asp	missense	Exon 3 of 14	NP_861448.2
	TMTC3	NM_001366574.1		c.19C>G	p.His7Asp	missense	Exon 3 of 14	NP_001353503.1
	TMTC3	NR_159381.1		n.408C>G		non_coding_transcript_exon	Exon 3 of 15

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMTC3	ENST00000266712.11	TSL:1 MANE Select	c.199C>G	p.His67Asp	missense	Exon 3 of 14	ENSP00000266712.6
	TMTC3	ENST00000547034.5	TSL:1	n.199C>G		non_coding_transcript_exon	Exon 3 of 12	ENSP00000448733.1
	TMTC3	ENST00000549011.5	TSL:4	c.199C>G	p.His67Asp	missense	Exon 3 of 4	ENSP00000447640.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Lissencephaly 8 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-9.0	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.53		Gain of catalytic residue at R71 (P = 0.0109)
MVP		0.95
MPC		1.2
ClinPred		1.0	D
GERP RS		5.9
gMVP		0.77
Mutation Taster		=30/70	disease causing (ClinVar)

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: rs754200057; hg19: chr12-88547077;