rs397518448

Variant names:

• chr1-165768763-GTC-G
• rs397518448
• ENST00000612311.4:c.140_141delGA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001256164.1(TMCO1):​c.140_141delGA​(p.Arg47ThrfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TMCO1 NM_001256164.1 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.124
• Publications: 5 publications found

Genes affected

TMCO1 (HGNC:18188): (transmembrane and coiled-coil domains 1) This locus encodes a transmembrane protein. Mutations at this locus have been associated with craniofacial dysmorphism, skeletal anomalies, and cognitive disability. Mutations at this locus have also been associated with open angle glaucoma blindness. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2012]

TMCO1-AS1 (HGNC:54046): (TMCO1 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256164.1. 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
	TMCO1	NM_019026.6	MANE Select	c.-14_-13delGA		5_prime_UTR	Exon 1 of 7	NP_061899.3	Q9UM00-1
	TMCO1	NM_001256164.1		c.140_141delGA	p.Arg47ThrfsTer18	frameshift	Exon 1 of 7	NP_001243093.1	B7Z591
	TMCO1	NM_001256165.1		c.-250_-249delGA		5_prime_UTR	Exon 1 of 7	NP_001243094.1	B7Z591

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCO1	ENST00000612311.4	TSL:1	c.140_141delGA	p.Arg47ThrfsTer52	frameshift	Exon 1 of 7	ENSP00000480514.1	Q9UM00-3
	TMCO1	ENST00000367881.11	TSL:1 MANE Select	c.-14_-13delGA		5_prime_UTR	Exon 1 of 7	ENSP00000356856.6	Q9UM00-1
	TMCO1	ENST00000628579.1	TSL:5	c.140_141delGA	p.Arg47ThrfsTer52	frameshift	Exon 1 of 4	ENSP00000485789.1	A0A0D9SEL8

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.12

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: rs397518448; hg19: chr1-165738000;