rs1913845

Variant names:

• chr1-165726342-C-T
• rs1913845
• ENST00000612311.4:c.*1681G>A

Variant summary

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

The ENST00000612311.4(TMCO1):​c.*1681G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 682,080 control chromosomes in the GnomAD database, including 23,923 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 0.24 (4528 hom., cov: 31)
  • Exomes 𝑓: 0.26 (19395 hom.)
• Consequence: TMCO1 ENST00000612311.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.162
• Publications: 8 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=-0.75).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMCO1	NR_045818.1	n.2342G>A		non_coding_transcript_exon_variant	Exon 7 of 7
TMCO1	NM_001256164.1	c.*1681G>A		3_prime_UTR_variant	Exon 7 of 7		NP_001243093.1
TMCO1	NM_001256165.1	c.*1681G>A		3_prime_UTR_variant	Exon 7 of 7		NP_001243094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMCO1	ENST00000612311.4	c.*1681G>A		3_prime_UTR_variant	Exon 7 of 7	1		ENSP00000480514.1
TMCO1	ENST00000481278.6	c.*1681G>A		3_prime_UTR_variant	Exon 7 of 7	3		ENSP00000462300.2

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36313 AN: 151794 Hom.: 4519 Cov.: 31

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.246

GnomAD2 exomes AF: 0.256 AC: 33351 AN: 130424 AF XY: 0.268

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.201

Gnomad ASJ exome AF: 0.229

Gnomad EAS exome AF: 0.141

Gnomad FIN exome AF: 0.205

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.249

GnomAD4 exome AF: 0.263 AC: 139576 AN: 530168 Hom.: 19395 Cov.: 0 AF XY: 0.271 AC XY: 77764 AN XY: 287282

African (AFR) AF: 0.184 AC: 2808 AN: 15246

American (AMR) AF: 0.206 AC: 7040 AN: 34120

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 4467 AN: 19494

East Asian (EAS) AF: 0.132 AC: 4107 AN: 31226

South Asian (SAS) AF: 0.355 AC: 21918 AN: 61686

European-Finnish (FIN) AF: 0.212 AC: 6670 AN: 31452

Middle Eastern (MID) AF: 0.290 AC: 670 AN: 2310

European-Non Finnish (NFE) AF: 0.277 AC: 84483 AN: 305330

Other (OTH) AF: 0.253 AC: 7413 AN: 29304

GnomAD4 genome AF: 0.239 AC: 36338 AN: 151912 Hom.: 4528 Cov.: 31 AF XY: 0.237 AC XY: 17630 AN XY: 74248

African (AFR) AF: 0.184 AC: 7631 AN: 41408

American (AMR) AF: 0.227 AC: 3464 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 831 AN: 3472

East Asian (EAS) AF: 0.145 AC: 752 AN: 5176

South Asian (SAS) AF: 0.340 AC: 1632 AN: 4798

European-Finnish (FIN) AF: 0.205 AC: 2156 AN: 10522

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.279 AC: 18935 AN: 67958

Other (OTH) AF: 0.246 AC: 520 AN: 2110

Alfa AF: 0.263 Hom.: 10214

Bravo AF: 0.234

Asia WGS AF: 0.256 AC: 888 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.83
PhyloP100		-0.16

Splicing

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

Other links and lift over

dbSNP: rs1913845; hg19: chr1-165695579;