rs6656194

Variant names:

• chr1-165795777-C-A
• rs6656194
• ENST00000580248.5:c.-183+1920G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000580248.5(TMCO1):​c.-183+1920G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 152,182 control chromosomes in the GnomAD database, including 2,104 homozygotes. 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 0.14 (2104 hom., cov: 32)
• Consequence: TMCO1 ENST00000580248.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.279
• Publications: 6 publications found

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, Laboratory for Molecular Medicine, Orphanet, PanelApp Australia, Illumina
• craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMCO1	ENST00000580248.5	c.-183+1920G>T		intron_variant	Intron 3 of 8	2		ENSP00000462588.1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20651 AN: 152064 Hom.: 2102 Cov.: 32

Gnomad AFR AF: 0.0656

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.146

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.136 AC: 20659 AN: 152182 Hom.: 2104 Cov.: 32 AF XY: 0.141 AC XY: 10457 AN XY: 74398

African (AFR) AF: 0.0656 AC: 2727 AN: 41544

American (AMR) AF: 0.168 AC: 2574 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 560 AN: 3470

East Asian (EAS) AF: 0.576 AC: 2981 AN: 5176

South Asian (SAS) AF: 0.137 AC: 658 AN: 4820

European-Finnish (FIN) AF: 0.187 AC: 1977 AN: 10568

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8721 AN: 68010

Other (OTH) AF: 0.144 AC: 304 AN: 2112

Alfa AF: 0.134 Hom.: 2372

Bravo AF: 0.135

Asia WGS AF: 0.280 AC: 973 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.5
DANN	Benign	0.48
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs6656194; hg19: chr1-165765014;