NM_019026.6:c.323+116A>G

Variant names:

• chr1-165751986-T-C
• rs7512095
• NM_019026.6:c.323+116A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019026.6(TMCO1):​c.323+116A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 838,792 control chromosomes in the GnomAD database, including 135,514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21532 hom., cov: 31)
  • Exomes 𝑓: 0.57 (113982 hom.)
• Consequence: TMCO1 NM_019026.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0580
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-165751986-T-C is Benign according to our data. Variant chr1-165751986-T-C is described in ClinVar as Benign. ClinVar VariationId is 1283707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.698 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.323+116A>G		intron	N/A	NP_061899.3	Q9UM00-1
	TMCO1	NM_001256164.1		c.374+116A>G		intron	N/A	NP_001243093.1	B7Z591
	TMCO1	NM_001256165.1		c.287+116A>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.323+116A>G		intron	N/A	ENSP00000356856.6	Q9UM00-1
	TMCO1	ENST00000612311.4	TSL:1	c.476+116A>G		intron	N/A	ENSP00000480514.1	Q9UM00-3
	TMCO1	ENST00000868463.1		c.323+116A>G		intron	N/A	ENSP00000538522.1

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79680 AN: 151772 Hom.: 21512 Cov.: 31

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.640

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.717

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.585

Gnomad OTH AF: 0.535

GnomAD4 exome AF: 0.569 AC: 391173 AN: 686900 Hom.: 113982 AF XY: 0.578 AC XY: 209089 AN XY: 361466

African (AFR) AF: 0.419 AC: 6993 AN: 16692

American (AMR) AF: 0.491 AC: 13882 AN: 28288

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 11812 AN: 19644

East Asian (EAS) AF: 0.346 AC: 11106 AN: 32138

South Asian (SAS) AF: 0.739 AC: 43878 AN: 59356

European-Finnish (FIN) AF: 0.474 AC: 22709 AN: 47922

Middle Eastern (MID) AF: 0.712 AC: 2189 AN: 3076

European-Non Finnish (NFE) AF: 0.582 AC: 259211 AN: 445660

Other (OTH) AF: 0.568 AC: 19393 AN: 34124

GnomAD4 genome AF: 0.525 AC: 79739 AN: 151892 Hom.: 21532 Cov.: 31 AF XY: 0.524 AC XY: 38899 AN XY: 74226

African (AFR) AF: 0.420 AC: 17405 AN: 41424

American (AMR) AF: 0.540 AC: 8232 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 2107 AN: 3470

East Asian (EAS) AF: 0.370 AC: 1916 AN: 5172

South Asian (SAS) AF: 0.718 AC: 3464 AN: 4822

European-Finnish (FIN) AF: 0.469 AC: 4920 AN: 10496

Middle Eastern (MID) AF: 0.695 AC: 203 AN: 292

European-Non Finnish (NFE) AF: 0.585 AC: 39770 AN: 67940

Other (OTH) AF: 0.541 AC: 1142 AN: 2112

Alfa AF: 0.533 Hom.: 2944

Bravo AF: 0.516

Asia WGS AF: 0.583 AC: 2024 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.4
DANN	Benign	0.86
PhyloP100		-0.058
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: rs7512095; hg19: chr1-165721223;