Genetic Variant TMCO1:c.324-9_324-8delTT (chr1-165743318-GAA-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_019026.6(TMCO1):c.324-9_324-8delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,325,004 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars).

Frequency

Genomes: 𝑓 0.000073 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0016 ( 0 hom. )

Consequence

TMCO1
NM_019026.6 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.01

Publications

0 publications found

Variant links:

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

TMCO1 links:

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ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TMCO1	NM_019026.6	MANE Select	c.324-9_324-8delTT	splice_region intron	N/A	NP_061899.3	Q9UM00-1
TMCO1	NM_001256164.1		c.375-9_375-8delTT	splice_region intron	N/A	NP_001243093.1	B7Z591
TMCO1	NM_001256165.1		c.288-9_288-8delTT	splice_region intron	N/A	NP_001243094.1	B7Z591

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TMCO1	ENST00000367881.11	TSL:1 MANE Select	c.324-9_324-8delTT	splice_region intron	N/A	ENSP00000356856.6	Q9UM00-1
TMCO1	ENST00000612311.4	TSL:1	c.477-9_477-8delTT	splice_region intron	N/A	ENSP00000480514.1	Q9UM00-3
TMCO1	ENST00000868463.1		c.447-9_447-8delTT	splice_region intron	N/A	ENSP00000538522.1

Frequencies

GnomAD3 genomes

AF:

0.0000836

AC:

AN:

95674

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000391

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00121

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000173

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000456

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00326

AC:

501

AN:

153726

AF XY:

0.00303

show subpopulations

Gnomad AFR exome

AF:

0.00388

Gnomad AMR exome

AF:

0.00543

Gnomad ASJ exome

AF:

0.00168

Gnomad EAS exome

AF:

0.00320

Gnomad FIN exome

AF:

0.00131

Gnomad NFE exome

AF:

0.00300

Gnomad OTH exome

AF:

0.00369

GnomAD4 exome

AF:

0.00159

AC:

1959

AN:

1229314

Hom.:

AF XY:

0.00154

AC XY:

946

AN XY:

615772

show subpopulations

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

African (AFR)

AF:

0.00183

AC:

AN:

27352

American (AMR)

AF:

0.00360

AC:

131

AN:

36394

Ashkenazi Jewish (ASJ)

AF:

0.00200

AC:

AN:

22534

East Asian (EAS)

AF:

0.00262

AC:

AN:

35092

South Asian (SAS)

AF:

0.00191

AC:

142

AN:

74224

European-Finnish (FIN)

AF:

0.00182

AC:

AN:

47240

Middle Eastern (MID)

AF:

0.00141

AC:

AN:

4258

European-Non Finnish (NFE)

AF:

0.00140

AC:

1305

AN:

930968

Other (OTH)

AF:

0.00199

AC:

102

AN:

51252

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.246

Heterozygous variant carriers

296

592

887

1183

1479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000732

AC:

AN:

95690

Hom.:

Cov.:

AF XY:

0.0000872

AC XY:

AN XY:

45892

show subpopulations

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

African (AFR)

AF:

0.0000390

AC:

AN:

25630

American (AMR)

AF:

0.00

AC:

AN:

9618

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2230

East Asian (EAS)

AF:

0.000909

AC:

AN:

3302

South Asian (SAS)

AF:

0.00

AC:

AN:

3242

European-Finnish (FIN)

AF:

0.000173

AC:

AN:

5792

Middle Eastern (MID)

AF:

0.00

AC:

AN:

190

European-Non Finnish (NFE)

AF:

0.0000456

AC:

AN:

43848

Other (OTH)

AF:

0.00

AC:

AN:

1302

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000387211), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00259

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.0

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

1-165743318-GAAAAAAA-GAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over