Genetic Variant ENST00000580248.5:c.-182-805T>C (chr1-165769074-A-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 ENST00000580248.5(TMCO1):c.-182-805T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,076 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: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TMCO1
ENST00000580248.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.43

Publications

13 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 links:

TMCO1-AS1 (HGNC:54046): (TMCO1 antisense RNA 1)

TMCO1-AS1 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=-0.89).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000580248.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TMCO1-AS1	NR_125374.1		n.146A>G	non_coding_transcript_exon	Exon 1 of 3
TMCO1	NM_019026.6	MANE Select	c.-323T>C	upstream_gene	N/A	NP_061899.3	Q9UM00-1
TMCO1	NM_001256164.1		c.-170T>C	upstream_gene	N/A	NP_001243093.1	B7Z591

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TMCO1	ENST00000580248.5	TSL:2	c.-182-805T>C	intron	N/A	ENSP00000462588.1	J3QQY2
TMCO1-AS1	ENST00000423121.1	TSL:2	n.146A>G	non_coding_transcript_exon	Exon 1 of 2
TMCO1	ENST00000367881.11	TSL:1 MANE Select	c.-323T>C	upstream_gene	N/A	ENSP00000356856.6	Q9UM00-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000174

AC:

AN:

573334

Hom.:

Cov.:

AF XY:

0.00000336

AC XY:

AN XY:

297374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

14826

American (AMR)

AF:

0.0000489

AC:

AN:

20440

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14800

East Asian (EAS)

AF:

0.00

AC:

AN:

31752

South Asian (SAS)

AF:

0.00

AC:

AN:

48814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29702

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2206

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

380682

Other (OTH)

AF:

0.00

AC:

AN:

30112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41404

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

2606

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.17

(source)

DANN

Benign

0.75

PhyloP100

-2.4

PromoterAI

0.040

Neutral

(source)

Splicing

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