1-165752099-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_019026.6(TMCO1):​c.323+3G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 31)

Consequence

TMCO1
NM_019026.6 splice_region, intron

Scores

2
Splicing: ADA: 0.9938
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.83
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-165752099-C-G is Pathogenic according to our data. Variant chr1-165752099-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 218899.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMCO1NM_019026.6 linkc.323+3G>C splice_region_variant, intron_variant Intron 5 of 6 ENST00000367881.11 NP_061899.3 Q9UM00-1
TMCO1NM_001256164.1 linkc.374+3G>C splice_region_variant, intron_variant Intron 5 of 6 NP_001243093.1 B7Z591
TMCO1NM_001256165.1 linkc.287+3G>C splice_region_variant, intron_variant Intron 5 of 6 NP_001243094.1 B7Z591
TMCO1NR_045818.1 linkn.417+3G>C splice_region_variant, intron_variant Intron 5 of 6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMCO1ENST00000367881.11 linkc.323+3G>C splice_region_variant, intron_variant Intron 5 of 6 1 NM_019026.6 ENSP00000356856.6 Q9UM00-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1 Pathogenic:1
Jan 15, 2014
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

Homozygous variant in a Turkish individual; RNA demonstrates missplicing due to intronic variant (Skipping of exon 5) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.30
CADD
Benign
18
DANN
Benign
0.89
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.76
SpliceAI score (max)
0.30
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.30
Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs372701032; hg19: chr1-165721336; API