NM_019026.6:c.324-8delT

Variant names:

• chr1-165743318-GA-G
• rs751227407
• NM_019026.6:c.324-8delT

Variant summary

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

The NM_019026.6(TMCO1):​c.324-8delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,155,014 control chromosomes in the GnomAD database, including 93 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.044 (66 hom., cov: 31)
  • Exomes 𝑓: 0.15 (27 hom.)
• Consequence: TMCO1 NM_019026.6 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 2.01
• 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 1-165743318-GA-G is Benign according to our data. Variant chr1-165743318-GA-G is described in ClinVar as Benign. ClinVar VariationId is 767722.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.109 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.324-8delT		splice_region intron	N/A	NP_061899.3	Q9UM00-1
	TMCO1	NM_001256164.1		c.375-8delT		splice_region intron	N/A	NP_001243093.1	B7Z591
	TMCO1	NM_001256165.1		c.288-8delT		splice_region 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.324-8delT		splice_region intron	N/A	ENSP00000356856.6	Q9UM00-1
	TMCO1	ENST00000612311.4	TSL:1	c.477-8delT		splice_region intron	N/A	ENSP00000480514.1	Q9UM00-3
	TMCO1	ENST00000868463.1		c.447-8delT		splice_region intron	N/A	ENSP00000538522.1

Frequencies

GnomAD3 genomes AF: 0.0435 AC: 4158 AN: 95506 Hom.: 65 Cov.: 31

Gnomad AFR AF: 0.0491

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.0632

Gnomad ASJ AF: 0.00673

Gnomad EAS AF: 0.0662

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0454

Gnomad MID AF: 0.0441

Gnomad NFE AF: 0.0294

Gnomad OTH AF: 0.0404

GnomAD2 exomes AF: 0.176 AC: 27107 AN: 153726 AF XY: 0.176

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.226

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.196

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.148 AC: 157240 AN: 1059494 Hom.: 27 Cov.: 0 AF XY: 0.149 AC XY: 78722 AN XY: 528270

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

African (AFR) AF: 0.160 AC: 3855 AN: 24072

American (AMR) AF: 0.189 AC: 6206 AN: 32912

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 2873 AN: 19402

East Asian (EAS) AF: 0.203 AC: 6170 AN: 30352

South Asian (SAS) AF: 0.171 AC: 11007 AN: 64400

European-Finnish (FIN) AF: 0.138 AC: 5803 AN: 42198

Middle Eastern (MID) AF: 0.166 AC: 620 AN: 3736

European-Non Finnish (NFE) AF: 0.142 AC: 113577 AN: 798370

Other (OTH) AF: 0.162 AC: 7129 AN: 44052

⚠️ 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: 0.0436 AC: 4167 AN: 95520 Hom.: 66 Cov.: 31 AF XY: 0.0483 AC XY: 2214 AN XY: 45792

African (AFR) AF: 0.0493 AC: 1262 AN: 25612

American (AMR) AF: 0.0640 AC: 614 AN: 9590

Ashkenazi Jewish (ASJ) AF: 0.00673 AC: 15 AN: 2230

East Asian (EAS) AF: 0.0661 AC: 218 AN: 3298

South Asian (SAS) AF: 0.119 AC: 385 AN: 3236

European-Finnish (FIN) AF: 0.0454 AC: 262 AN: 5768

Middle Eastern (MID) AF: 0.0421 AC: 8 AN: 190

European-Non Finnish (NFE) AF: 0.0295 AC: 1289 AN: 43764

Other (OTH) AF: 0.0409 AC: 53 AN: 1296

Alfa AF: 0.0549 Hom.: 1

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
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: rs751227407; hg19: chr1-165712555;