rs6426940

Variant names:

• chr1-165764246-T-C
• rs6426940
• NM_019026.6:c.148+3946A>G

Variant summary

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

The NM_019026.6(TMCO1):​c.148+3946A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 152,130 control chromosomes in the GnomAD database, including 21,777 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 0.53 (21777 hom., cov: 33)
• Consequence: TMCO1 NM_019026.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.264
• Publications: 4 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, 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCO1	NM_019026.6	MANE Select	c.148+3946A>G		intron	N/A	NP_061899.3	Q9UM00-1
	TMCO1	NM_001256164.1		c.199+3946A>G		intron	N/A	NP_001243093.1	B7Z591
	TMCO1	NM_001256165.1		c.112+3946A>G		intron	N/A	NP_001243094.1	B7Z591

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCO1	ENST00000367881.11	TSL:1 MANE Select	c.148+3946A>G		intron	N/A	ENSP00000356856.6	Q9UM00-1
	TMCO1	ENST00000612311.4	TSL:1	c.301+3946A>G		intron	N/A	ENSP00000480514.1	Q9UM00-3
	TMCO1	ENST00000868463.1		c.148+3946A>G		intron	N/A	ENSP00000538522.1

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80276 AN: 152012 Hom.: 21757 Cov.: 33

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.640

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.717

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.538

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

GnomAD4 genome AF: 0.528 AC: 80337 AN: 152130 Hom.: 21777 Cov.: 33 AF XY: 0.527 AC XY: 39219 AN XY: 74370

African (AFR) AF: 0.430 AC: 17860 AN: 41516

American (AMR) AF: 0.542 AC: 8276 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 2102 AN: 3466

East Asian (EAS) AF: 0.369 AC: 1910 AN: 5170

South Asian (SAS) AF: 0.718 AC: 3466 AN: 4824

European-Finnish (FIN) AF: 0.469 AC: 4966 AN: 10582

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.586 AC: 39820 AN: 67982

Other (OTH) AF: 0.543 AC: 1148 AN: 2114

Alfa AF: 0.532 Hom.: 3891

Bravo AF: 0.520

Asia WGS AF: 0.584 AC: 2030 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.1
DANN	Benign	0.64
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6426940; hg19: chr1-165733483;