1-165728260-CTTT-C

Variant names:

• chr1-165728260-CTTT-C
• rs397967679
• NM_019026.6:c.469-142_469-140delAAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_019026.6(TMCO1):​c.469-142_469-140delAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 463,370 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: TMCO1 NM_019026.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.50
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.469-142_469-140delAAA		intron	N/A	NP_061899.3	Q9UM00-1
	TMCO1	NM_001256164.1		c.520-142_520-140delAAA		intron	N/A	NP_001243093.1	B7Z591
	TMCO1	NM_001256165.1		c.433-142_433-140delAAA		intron	N/A	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.469-142_469-140delAAA		intron	N/A	ENSP00000356856.6	Q9UM00-1
	TMCO1	ENST00000612311.4	TSL:1	c.622-142_622-140delAAA		intron	N/A	ENSP00000480514.1	Q9UM00-3
	TMCO1	ENST00000868463.1		c.592-142_592-140delAAA		intron	N/A	ENSP00000538522.1

Frequencies

GnomAD3 genomes AF: 0.00000693 AC: 1 AN: 144234 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000153

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000288 AC: 92 AN: 319136 Hom.: 0 AF XY: 0.000321 AC XY: 57 AN XY: 177838

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

African (AFR) AF: 0.000251 AC: 2 AN: 7958

American (AMR) AF: 0.000198 AC: 4 AN: 20236

Ashkenazi Jewish (ASJ) AF: 0.000565 AC: 5 AN: 8854

East Asian (EAS) AF: 0.000228 AC: 3 AN: 13182

South Asian (SAS) AF: 0.000180 AC: 9 AN: 50046

European-Finnish (FIN) AF: 0.000184 AC: 3 AN: 16266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1154

European-Non Finnish (NFE) AF: 0.000337 AC: 63 AN: 186702

Other (OTH) AF: 0.000204 AC: 3 AN: 14738

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000693 AC: 1 AN: 144234 Hom.: 0 Cov.: 31 AF XY: 0.0000143 AC XY: 1 AN XY: 69938

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

African (AFR) AF: 0.00 AC: 0 AN: 39552

American (AMR) AF: 0.00 AC: 0 AN: 14382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3354

East Asian (EAS) AF: 0.00 AC: 0 AN: 5008

South Asian (SAS) AF: 0.00 AC: 0 AN: 4540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.0000153 AC: 1 AN: 65382

Other (OTH) AF: 0.00 AC: 0 AN: 1954

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism

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: rs397967679; hg19: chr1-165697497;