chr12-88148330-C-T

Variant names:

• chr12-88148330-C-T
• rs1592720758
• NM_181783.4:c.15C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_181783.4(TMTC3):​c.15C>T​(p.Asn5Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMTC3 NM_181783.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.617
• Publications: 0 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: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-88148330-C-T is Benign according to our data. Variant chr12-88148330-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 796286.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.617 with no splicing effect.

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.15C>T	p.Asn5Asn	synonymous	Exon 2 of 14	NP_861448.2	Q6ZXV5-2
	TMTC3	NM_001366579.1		c.15C>T	p.Asn5Asn	synonymous	Exon 2 of 13	NP_001353508.1
	TMTC3	NM_001366574.1		c.-77-89C>T		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.15C>T	p.Asn5Asn	synonymous	Exon 2 of 14	ENSP00000266712.6	Q6ZXV5-2
	TMTC3	ENST00000547034.5	TSL:1	n.15C>T		non_coding_transcript_exon	Exon 2 of 12	ENSP00000448733.1	F8VRY4
	TMTC3	ENST00000869786.1		c.15C>T	p.Asn5Asn	synonymous	Exon 2 of 14	ENSP00000539845.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456932 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 724476

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33244

American (AMR) AF: 0.00 AC: 0 AN: 43962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25938

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 84800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110278

Other (OTH) AF: 0.00 AC: 0 AN: 60174

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.7
DANN	Benign	0.52
PhyloP100		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1592720758; hg19: chr12-88542107;