NM_019026.6:c.469-140dupA

Variant names:

• chr1-165728260-C-CT
• rs397967679
• NM_019026.6:c.469-140dupA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_019026.6(TMCO1):​c.469-140dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0818 in 436,994 control chromosomes in the GnomAD database, including 73 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (71 hom., cov: 31)
  • Exomes 𝑓: 0.11 (2 hom.)
• Consequence: TMCO1 NM_019026.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.355
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 1-165728260-C-CT is Benign according to our data. Variant chr1-165728260-C-CT is described in ClinVar as Benign. ClinVar VariationId is 1277148.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.052 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.469-140dupA		intron	N/A	NP_061899.3	Q9UM00-1
	TMCO1	NM_001256164.1		c.520-140dupA		intron	N/A	NP_001243093.1	B7Z591
	TMCO1	NM_001256165.1		c.433-140dupA		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.469-140_469-139insA		intron	N/A	ENSP00000356856.6	Q9UM00-1
	TMCO1	ENST00000612311.4	TSL:1	c.622-140_622-139insA		intron	N/A	ENSP00000480514.1	Q9UM00-3
	TMCO1	ENST00000868463.1		c.592-140_592-139insA		intron	N/A	ENSP00000538522.1

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3479 AN: 144110 Hom.: 72 Cov.: 31

Gnomad AFR AF: 0.0538

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.0254

Gnomad SAS AF: 0.00485

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.0395

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0184

GnomAD4 exome AF: 0.110 AC: 32242 AN: 292834 Hom.: 2 AF XY: 0.111 AC XY: 18029 AN XY: 162998

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.145 AC: 1067 AN: 7336

American (AMR) AF: 0.103 AC: 1916 AN: 18540

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 1003 AN: 8248

East Asian (EAS) AF: 0.106 AC: 1283 AN: 12078

South Asian (SAS) AF: 0.108 AC: 4805 AN: 44514

European-Finnish (FIN) AF: 0.0873 AC: 1326 AN: 15182

Middle Eastern (MID) AF: 0.0987 AC: 105 AN: 1064

European-Non Finnish (NFE) AF: 0.111 AC: 19196 AN: 172354

Other (OTH) AF: 0.114 AC: 1541 AN: 13518

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0242 AC: 3487 AN: 144160 Hom.: 71 Cov.: 31 AF XY: 0.0231 AC XY: 1614 AN XY: 69938

African (AFR) AF: 0.0539 AC: 2137 AN: 39616

American (AMR) AF: 0.0145 AC: 209 AN: 14390

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 112 AN: 3350

East Asian (EAS) AF: 0.0250 AC: 125 AN: 4996

South Asian (SAS) AF: 0.00442 AC: 20 AN: 4522

European-Finnish (FIN) AF: 0.0113 AC: 100 AN: 8822

Middle Eastern (MID) AF: 0.0396 AC: 11 AN: 278

European-Non Finnish (NFE) AF: 0.0113 AC: 736 AN: 65324

Other (OTH) AF: 0.0188 AC: 37 AN: 1972

Alfa AF: 0.00285 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism

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: rs397967679; hg19: chr1-165697497;