chr1-165728095-GGC-G

Variant names:

• chr1-165728095-GGC-G
• rs1558027212
• NM_019026.6:c.493_494delGC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_019026.6(TMCO1):​c.493_494delGC​(p.Ala165ProfsTer53) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMCO1 NM_019026.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.50
• Publications: 0 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 Gene-Disease associations (from GenCC):

• cerebrofaciothoracic dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Illumina, Laboratory for Molecular Medicine, Orphanet
• craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.131 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-165728095-GGC-G is Pathogenic according to our data. Variant chr1-165728095-GGC-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 598949.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019026.6. 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.493_494delGC	p.Ala165ProfsTer53	frameshift	Exon 7 of 7	NP_061899.3	Q9UM00-1
	TMCO1	NM_001256164.1		c.544_545delGC	p.Ala182ProfsTer53	frameshift	Exon 7 of 7	NP_001243093.1	B7Z591
	TMCO1	NM_001256165.1		c.457_458delGC	p.Ala153ProfsTer53	frameshift	Exon 7 of 7	NP_001243094.1	B7Z591

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCO1	ENST00000367881.11	TSL:1 MANE Select	c.493_494delGC	p.Ala165ProfsTer53	frameshift	Exon 7 of 7	ENSP00000356856.6	Q9UM00-1
	TMCO1	ENST00000612311.4	TSL:1	c.646_647delGC	p.Ala216ProfsTer53	frameshift	Exon 7 of 7	ENSP00000480514.1	Q9UM00-3
	TMCO1	ENST00000868463.1		c.616_617delGC	p.Ala206ProfsTer53	frameshift	Exon 8 of 8	ENSP00000538522.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5

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: rs1558027212; hg19: chr1-165697332;