NM_019026.6:c.324-8dupT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_019026.6(TMCO1):​c.324-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 31)
  • Exomes 𝑓: 0.17 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMCO1 NM_019026.6 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 1-165743318-G-GA is Benign according to our data. Variant chr1-165743318-G-GA is described in ClinVar as Benign. ClinVar VariationId is 770495.Status of the report is criteria_provided_single_submitter, 1 stars.

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.324-8dupT		splice_region intron	N/A	NP_061899.3	Q9UM00-1
	TMCO1	NM_001256164.1		c.375-8dupT		splice_region intron	N/A	NP_001243093.1	B7Z591
	TMCO1	NM_001256165.1		c.288-8dupT		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.324-8_324-7insT		splice_region intron	N/A	ENSP00000356856.6	Q9UM00-1
	TMCO1	ENST00000612311.4	TSL:1	c.477-8_477-7insT		splice_region intron	N/A	ENSP00000480514.1	Q9UM00-3
	TMCO1	ENST00000868463.1		c.447-8_447-7insT		splice_region intron	N/A	ENSP00000538522.1

Frequencies

GnomAD3 genomes AF: 0.00341 AC: 326 AN: 95570 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00146

Gnomad ASJ AF: 0.000898

Gnomad EAS AF: 0.00151

Gnomad SAS AF: 0.00703

Gnomad FIN AF: 0.00711

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.00388

GnomAD2 exomes AF: 0.0849 AC: 13047 AN: 153726 AF XY: 0.0833

Gnomad AFR exome AF: 0.0931

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.110

Gnomad FIN exome AF: 0.0490

Gnomad NFE exome AF: 0.0792

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.174 AC: 181488 AN: 1044954 Hom.: 0 Cov.: 0 AF XY: 0.167 AC XY: 87418 AN XY: 522108

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

African (AFR) AF: 0.167 AC: 3928 AN: 23522

American (AMR) AF: 0.0880 AC: 2913 AN: 33100

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 2952 AN: 19714

East Asian (EAS) AF: 0.134 AC: 4135 AN: 30866

South Asian (SAS) AF: 0.113 AC: 7037 AN: 62368

European-Finnish (FIN) AF: 0.0954 AC: 4126 AN: 43232

Middle Eastern (MID) AF: 0.139 AC: 525 AN: 3766

European-Non Finnish (NFE) AF: 0.189 AC: 148446 AN: 784464

Other (OTH) AF: 0.169 AC: 7426 AN: 43922

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00345 AC: 330 AN: 95584 Hom.: 0 Cov.: 31 AF XY: 0.00402 AC XY: 184 AN XY: 45826

African (AFR) AF: 0.00613 AC: 157 AN: 25614

American (AMR) AF: 0.00146 AC: 14 AN: 9600

Ashkenazi Jewish (ASJ) AF: 0.000898 AC: 2 AN: 2228

East Asian (EAS) AF: 0.00152 AC: 5 AN: 3300

South Asian (SAS) AF: 0.00710 AC: 23 AN: 3238

European-Finnish (FIN) AF: 0.00711 AC: 41 AN: 5770

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 190

European-Non Finnish (NFE) AF: 0.00187 AC: 82 AN: 43816

Other (OTH) AF: 0.00463 AC: 6 AN: 1296

Alfa AF: 0.0408 Hom.: 1

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		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;