Genetic Variant TMCO1:c.469-140dupA (chr1-165728260-C-CT) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_019026.6(TMCO1):c.469-140dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0818 in 436,994 control chromosomes in the GnomAD database, including 73 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.024 ( 71 hom., cov: 31)

Exomes 𝑓: 0.11 ( 2 hom. )

Consequence

TMCO1
NM_019026.6 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.355

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 1-165728260-C-CT is Benign according to our data. Variant chr1-165728260-C-CT is described in ClinVar as Benign. ClinVar VariationId is 1277148.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.052 is higher than 0.05.

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.469-140dupA	intron	N/A	NP_061899.3	Q9UM00-1
TMCO1	NM_001256164.1		c.520-140dupA	intron	N/A	NP_001243093.1	B7Z591
TMCO1	NM_001256165.1		c.433-140dupA	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.469-140_469-139insA	intron	N/A	ENSP00000356856.6	Q9UM00-1
TMCO1	ENST00000612311.4	TSL:1	c.622-140_622-139insA	intron	N/A	ENSP00000480514.1	Q9UM00-3
TMCO1	ENST00000868463.1		c.592-140_592-139insA	intron	N/A	ENSP00000538522.1

Frequencies

GnomAD3 genomes

AF:

0.0241

AC:

3479

AN:

144110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0538

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0144

Gnomad ASJ

AF:

0.0334

Gnomad EAS

AF:

0.0254

Gnomad SAS

AF:

0.00485

Gnomad FIN

AF:

0.0113

Gnomad MID

AF:

0.0395

Gnomad NFE

AF:

0.0112

Gnomad OTH

AF:

0.0184

GnomAD4 exome

AF:

0.110

AC:

32242

AN:

292834

Hom.:

AF XY:

0.111

AC XY:

18029

AN XY:

162998

show subpopulations

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

African (AFR)

AF:

0.145

AC:

1067

AN:

7336

American (AMR)

AF:

0.103

AC:

1916

AN:

18540

Ashkenazi Jewish (ASJ)

AF:

0.122

AC:

1003

AN:

8248

East Asian (EAS)

AF:

0.106

AC:

1283

AN:

12078

South Asian (SAS)

AF:

0.108

AC:

4805

AN:

44514

European-Finnish (FIN)

AF:

0.0873

AC:

1326

AN:

15182

Middle Eastern (MID)

AF:

0.0987

AC:

105

AN:

1064

European-Non Finnish (NFE)

AF:

0.111

AC:

19196

AN:

172354

Other (OTH)

AF:

0.114

AC:

1541

AN:

13518

⚠️ 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: 0.283

Heterozygous variant carriers

2987

5974

8960

11947

14934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

244

488

732

976

1220

<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:

0.0242

AC:

3487

AN:

144160

Hom.:

Cov.:

AF XY:

0.0231

AC XY:

1614

AN XY:

69938

show subpopulations

African (AFR)

AF:

0.0539

AC:

2137

AN:

39616

American (AMR)

AF:

0.0145

AC:

209

AN:

14390

Ashkenazi Jewish (ASJ)

AF:

0.0334

AC:

112

AN:

3350

East Asian (EAS)

AF:

0.0250

AC:

125

AN:

4996

South Asian (SAS)

AF:

0.00442

AC:

AN:

4522

European-Finnish (FIN)

AF:

0.0113

AC:

100

AN:

8822

Middle Eastern (MID)

AF:

0.0396

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.0113

AC:

736

AN:

65324

Other (OTH)

AF:

0.0188

AC:

AN:

1972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

149

298

448

597

746

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.00285

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.35

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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1-165728260-CTTTT-CTTTTT

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