1-165728260-CTTTT-CTT

Variant names:

• chr1-165728260-CTT-C
• rs397967679
• NM_019026.6:c.469-141_469-140delAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_019026.6(TMCO1):​c.469-141_469-140delAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 454,156 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 0.000069 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0046 (0 hom.)
• Consequence: TMCO1 NM_019026.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.355
• 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 2 ACMG points.

• PM2: Variant has high frequency in the AMR (0.00556) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

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.469-141_469-140delAA		intron	N/A	NP_061899.3	Q9UM00-1
	TMCO1	NM_001256164.1		c.520-141_520-140delAA		intron	N/A	NP_001243093.1	B7Z591
	TMCO1	NM_001256165.1		c.433-141_433-140delAA		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.469-141_469-140delAA		intron	N/A	ENSP00000356856.6	Q9UM00-1
	TMCO1	ENST00000612311.4	TSL:1	c.622-141_622-140delAA		intron	N/A	ENSP00000480514.1	Q9UM00-3
	TMCO1	ENST00000868463.1		c.592-141_592-140delAA		intron	N/A	ENSP00000538522.1

Frequencies

GnomAD3 genomes AF: 0.0000624 AC: 9 AN: 144188 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: 0.000338

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000918

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00458 AC: 1419 AN: 309918 Hom.: 0 AF XY: 0.00460 AC XY: 795 AN XY: 172788

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

African (AFR) AF: 0.00348 AC: 27 AN: 7750

American (AMR) AF: 0.00648 AC: 127 AN: 19606

Ashkenazi Jewish (ASJ) AF: 0.00628 AC: 54 AN: 8598

East Asian (EAS) AF: 0.00342 AC: 44 AN: 12862

South Asian (SAS) AF: 0.00343 AC: 166 AN: 48346

European-Finnish (FIN) AF: 0.00405 AC: 64 AN: 15810

Middle Eastern (MID) AF: 0.00445 AC: 5 AN: 1124

European-Non Finnish (NFE) AF: 0.00476 AC: 864 AN: 181526

Other (OTH) AF: 0.00476 AC: 68 AN: 14296

⚠️ 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: 0.0000693 AC: 10 AN: 144238 Hom.: 0 Cov.: 31 AF XY: 0.000114 AC XY: 8 AN XY: 69972

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

African (AFR) AF: 0.0000252 AC: 1 AN: 39622

American (AMR) AF: 0.00 AC: 0 AN: 14386

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4994

South Asian (SAS) AF: 0.00 AC: 0 AN: 4522

European-Finnish (FIN) AF: 0.000338 AC: 3 AN: 8874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.0000918 AC: 6 AN: 65346

Other (OTH) AF: 0.00 AC: 0 AN: 1972

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000000998091), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.35
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;