1-165743318-GAAAAAAA-GAAAAAAAAA

Variant names:

• chr1-165743318-G-GAA
• rs751227407
• NM_019026.6:c.324-9_324-8dupTT

Variant summary

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

The NM_019026.6(TMCO1):​c.324-9_324-8dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000491 in 1,338,842 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 0.000010 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: TMCO1 NM_019026.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.01
• 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.324-9_324-8dupTT		splice_region intron	N/A	NP_061899.3	Q9UM00-1
	TMCO1	NM_001256164.1		c.375-9_375-8dupTT		splice_region intron	N/A	NP_001243093.1	B7Z591
	TMCO1	NM_001256165.1		c.288-9_288-8dupTT		splice_region 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.324-8_324-7insTT		splice_region intron	N/A	ENSP00000356856.6	Q9UM00-1
	TMCO1	ENST00000612311.4	TSL:1	c.477-8_477-7insTT		splice_region intron	N/A	ENSP00000480514.1	Q9UM00-3
	TMCO1	ENST00000868463.1		c.447-8_447-7insTT		splice_region intron	N/A	ENSP00000538522.1

Frequencies

GnomAD3 genomes AF: 0.0000105 AC: 1 AN: 95686 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: 0.0000228

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000703 AC: 108 AN: 153726 AF XY: 0.000618

Gnomad AFR exome AF: 0.000918

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.000168

Gnomad EAS exome AF: 0.000549

Gnomad FIN exome AF: 0.000197

Gnomad NFE exome AF: 0.000836

Gnomad OTH exome AF: 0.000284

GnomAD4 exome AF: 0.000528 AC: 656 AN: 1243156 Hom.: 0 Cov.: 0 AF XY: 0.000508 AC XY: 316 AN XY: 622510

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

African (AFR) AF: 0.000578 AC: 16 AN: 27680

American (AMR) AF: 0.000542 AC: 20 AN: 36894

Ashkenazi Jewish (ASJ) AF: 0.000350 AC: 8 AN: 22838

East Asian (EAS) AF: 0.000309 AC: 11 AN: 35610

South Asian (SAS) AF: 0.000294 AC: 22 AN: 74790

European-Finnish (FIN) AF: 0.000334 AC: 16 AN: 47900

Middle Eastern (MID) AF: 0.000463 AC: 2 AN: 4320

European-Non Finnish (NFE) AF: 0.000573 AC: 539 AN: 941248

Other (OTH) AF: 0.000424 AC: 22 AN: 51876

⚠️ 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: 0.0000105 AC: 1 AN: 95686 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 45864

⚠️ 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: 25574

American (AMR) AF: 0.00 AC: 0 AN: 9598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2230

East Asian (EAS) AF: 0.00 AC: 0 AN: 3312

South Asian (SAS) AF: 0.00 AC: 0 AN: 3274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 204

European-Non Finnish (NFE) AF: 0.0000228 AC: 1 AN: 43870

Other (OTH) AF: 0.00 AC: 0 AN: 1294

⚠️ 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: 0.00134 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs751227407; hg19: chr1-165712555;