Genetic Variant NM_019026.6:c.324-7C>T (chr1-165743318-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_019026.6(TMCO1):c.324-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0082 ( 0 hom., cov: 28)

Exomes 𝑓: 0.035 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TMCO1
NM_019026.6 splice_region, intron

Scores

Splicing: ADA: 0.00001840

Clinical Significance

Likely benign criteria provided, single submitter B:3

Conservation

PhyloP100: 0.652

Publications

0 publications found

Variant links:

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

TMCO1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 1-165743318-G-A is Benign according to our data. Variant chr1-165743318-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1156516.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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TMCO1	NM_019026.6	MANE Select	c.324-7C>T	splice_region intron	N/A	NP_061899.3	Q9UM00-1
TMCO1	NM_001256164.1		c.375-7C>T	splice_region intron	N/A	NP_001243093.1	B7Z591
TMCO1	NM_001256165.1		c.288-7C>T	splice_region intron	N/A	NP_001243094.1	B7Z591

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TMCO1	ENST00000367881.11	TSL:1 MANE Select	c.324-7C>T	splice_region intron	N/A	ENSP00000356856.6	Q9UM00-1
TMCO1	ENST00000612311.4	TSL:1	c.477-7C>T	splice_region intron	N/A	ENSP00000480514.1	Q9UM00-3
TMCO1	ENST00000868463.1		c.447-7C>T	splice_region intron	N/A	ENSP00000538522.1

Frequencies

GnomAD3 genomes

AF:

0.00816

AC:

770

AN:

94310

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00531

Gnomad AMI

AF:

0.00958

Gnomad AMR

AF:

0.00513

Gnomad ASJ

AF:

0.00817

Gnomad EAS

AF:

0.00645

Gnomad SAS

AF:

0.00338

Gnomad FIN

AF:

0.0231

Gnomad MID

AF:

0.0149

Gnomad NFE

AF:

0.00905

Gnomad OTH

AF:

0.00544

GnomAD2 exomes

AF:

0.240

AC:

36836

AN:

153726

AF XY:

0.243

show subpopulations

Gnomad AFR exome

AF:

0.235

Gnomad AMR exome

AF:

0.175

Gnomad ASJ exome

AF:

0.210

Gnomad EAS exome

AF:

0.198

Gnomad FIN exome

AF:

0.321

Gnomad NFE exome

AF:

0.253

Gnomad OTH exome

AF:

0.209

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0352

AC:

43837

AN:

1247094

Hom.:

Cov.:

AF XY:

0.0403

AC XY:

25145

AN XY:

624102

show subpopulations

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

African (AFR)

AF:

0.0407

AC:

1129

AN:

27754

American (AMR)

AF:

0.132

AC:

4839

AN:

36642

Ashkenazi Jewish (ASJ)

AF:

0.0690

AC:

1576

AN:

22832

East Asian (EAS)

AF:

0.0420

AC:

1499

AN:

35684

South Asian (SAS)

AF:

0.0862

AC:

6409

AN:

74334

European-Finnish (FIN)

AF:

0.164

AC:

7830

AN:

47848

Middle Eastern (MID)

AF:

0.0608

AC:

263

AN:

4324

European-Non Finnish (NFE)

AF:

0.0198

AC:

18767

AN:

945670

Other (OTH)

AF:

0.0293

AC:

1525

AN:

52006

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.389

Heterozygous variant carriers

1652

3304

4955

6607

8259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

300

600

900

1200

1500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00818

AC:

772

AN:

94324

Hom.:

Cov.:

AF XY:

0.00964

AC XY:

436

AN XY:

45212

show subpopulations

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

African (AFR)

AF:

0.00530

AC:

134

AN:

25282

American (AMR)

AF:

0.00512

AC:

AN:

9564

Ashkenazi Jewish (ASJ)

AF:

0.00817

AC:

AN:

2202

East Asian (EAS)

AF:

0.00678

AC:

AN:

3246

South Asian (SAS)

AF:

0.00341

AC:

AN:

3226

European-Finnish (FIN)

AF:

0.0231

AC:

132

AN:

5714

Middle Eastern (MID)

AF:

0.0160

AC:

AN:

188

European-Non Finnish (NFE)

AF:

0.00907

AC:

391

AN:

43086

Other (OTH)

AF:

0.00541

AC:

AN:

1294

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.279

Heterozygous variant carriers

166

248

331

414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0914

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

6.7

(source)

DANN

Benign

0.35

PhyloP100

0.65

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000018

dbscSNV1_RF

Benign

0.0020

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over