Genetic Variant TMCO1:c.323+116A>C (chr1-165751986-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_019026.6(TMCO1):c.323+116A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 688,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

TMCO1
NM_019026.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0580

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

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.323+116A>C	intron	N/A	NP_061899.3	Q9UM00-1
TMCO1	NM_001256164.1		c.374+116A>C	intron	N/A	NP_001243093.1	B7Z591
TMCO1	NM_001256165.1		c.287+116A>C	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.323+116A>C	intron	N/A	ENSP00000356856.6	Q9UM00-1
TMCO1	ENST00000612311.4	TSL:1	c.476+116A>C	intron	N/A	ENSP00000480514.1	Q9UM00-3
TMCO1	ENST00000868463.1		c.323+116A>C	intron	N/A	ENSP00000538522.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000145

AC:

AN:

688314

Hom.:

AF XY:

0.00000276

AC XY:

AN XY:

362170

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

16738

American (AMR)

AF:

0.00

AC:

AN:

28324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19678

East Asian (EAS)

AF:

0.00

AC:

AN:

32164

South Asian (SAS)

AF:

0.00

AC:

AN:

59388

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47960

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3084

European-Non Finnish (NFE)

AF:

0.00000224

AC:

AN:

446794

Other (OTH)

AF:

0.00

AC:

AN:

34184

⚠️ 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: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.2

(source)

DANN

Benign

0.85

PhyloP100

-0.058

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over