1-165743318-GAAAAAAA-GAAAA

Variant names:

• chr1-165743318-GAAA-G
• rs751227407
• NM_019026.6:c.324-10_324-8delTTT

Variant summary

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

The NM_019026.6(TMCO1):​c.324-10_324-8delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000684 in 1,345,488 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. 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: 0.000073 (0 hom.)
• Consequence: TMCO1 NM_019026.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.54
• 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: Very rare variant in population databases, with high coverage

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.324-10_324-8delTTT		splice_region intron	N/A	NP_061899.3	Q9UM00-1
	TMCO1	NM_001256164.1		c.375-10_375-8delTTT		splice_region intron	N/A	NP_001243093.1	B7Z591
	TMCO1	NM_001256165.1		c.288-10_288-8delTTT		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.324-10_324-8delTTT		splice_region intron	N/A	ENSP00000356856.6	Q9UM00-1
	TMCO1	ENST00000612311.4	TSL:1	c.477-10_477-8delTTT		splice_region intron	N/A	ENSP00000480514.1	Q9UM00-3
	TMCO1	ENST00000868463.1		c.447-10_447-8delTTT		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: 0.000173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000111 AC: 17 AN: 153726 AF XY: 0.0000833

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000987

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000183

Gnomad FIN exome AF: 0.000197

Gnomad NFE exome AF: 0.000144

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000728 AC: 91 AN: 1249802 Hom.: 0 AF XY: 0.0000527 AC XY: 33 AN XY: 625696

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

African (AFR) AF: 0.000108 AC: 3 AN: 27834

American (AMR) AF: 0.000162 AC: 6 AN: 37006

Ashkenazi Jewish (ASJ) AF: 0.0000436 AC: 1 AN: 22956

East Asian (EAS) AF: 0.0000279 AC: 1 AN: 35796

South Asian (SAS) AF: 0.0000399 AC: 3 AN: 75112

European-Finnish (FIN) AF: 0.000333 AC: 16 AN: 48012

Middle Eastern (MID) AF: 0.000231 AC: 1 AN: 4334

European-Non Finnish (NFE) AF: 0.0000581 AC: 55 AN: 946624

Other (OTH) AF: 0.0000959 AC: 5 AN: 52128

⚠️ 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: 0.0000218 AC XY: 1 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: 25572

American (AMR) AF: 0.00 AC: 0 AN: 9600

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: 0.000173 AC: 1 AN: 5792

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 43872

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.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5
Mutation Taster		=99/1	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: rs751227407; hg19: chr1-165712555;