Genetic Variant COL12A1:c.9182-95_9182-92dupTATA (chr6-75086648-G-GTATA) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_004370.6(COL12A1):c.9182-95_9182-92dupTATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 288,876 control chromosomes in the GnomAD database, including 101 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.023 ( 101 hom., cov: 0)

Exomes 𝑓: 0.00096 ( 0 hom. )

Consequence

COL12A1
NM_004370.6 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.00

Publications

0 publications found

Variant links:

Genes affected

COL12A1 (HGNC:2188): (collagen type XII alpha 1 chain) This gene encodes the alpha chain of type XII collagen, a member of the FACIT (fibril-associated collagens with interrupted triple helices) collagen family. Type XII collagen is a homotrimer found in association with type I collagen, an association that is thought to modify the interactions between collagen I fibrils and the surrounding matrix. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

COL12A1 Gene-Disease associations (from GenCC):

Bethlem myopathy 2
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
Bethlem myopathy 2
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Illumina, Genomics England PanelApp
Ullrich congenital muscular dystrophy 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Bethlem myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ullrich congenital muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

COL12A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 6-75086648-G-GTATA is Benign according to our data. Variant chr6-75086648-G-GTATA is described in ClinVar as [Benign]. Clinvar id is 1228153.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6 link	c.9182-95_9182-92dupTATA		intron_variant	Intron 65 of 65	ENST00000322507.13	NP_004361.3	Q99715-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13 link	c.9182-92_9182-91insTATA		intron_variant	Intron 65 of 65	1	NM_004370.6	ENSP00000325146.8		Q99715-1

Frequencies

GnomAD3 genomes

AF:

0.0233

AC:

3296

AN:

141596

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0753

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0125

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0127

Gnomad SAS

AF:

0.00181

Gnomad FIN

AF:

0.000124

Gnomad MID

AF:

0.00694

Gnomad NFE

AF:

0.00165

Gnomad OTH

AF:

0.0182

GnomAD4 exome

AF:

0.000957

AC:

141

AN:

147286

Hom.:

AF XY:

0.000974

AC XY:

AN XY:

82110

show subpopulations

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

African (AFR)

AF:

0.0106

AC:

AN:

2546

American (AMR)

AF:

0.00155

AC:

AN:

6466

Ashkenazi Jewish (ASJ)

AF:

0.000234

AC:

AN:

4270

East Asian (EAS)

AF:

0.000868

AC:

AN:

5762

South Asian (SAS)

AF:

0.00101

AC:

AN:

12822

European-Finnish (FIN)

AF:

0.000208

AC:

AN:

19244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

542

European-Non Finnish (NFE)

AF:

0.000763

AC:

AN:

89114

Other (OTH)

AF:

0.00199

AC:

AN:

6520

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.331

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0233

AC:

3303

AN:

141590

Hom.:

101

Cov.:

AF XY:

0.0236

AC XY:

1617

AN XY:

68548

show subpopulations

African (AFR)

AF:

0.0754

AC:

2910

AN:

38610

American (AMR)

AF:

0.0125

AC:

177

AN:

14162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3366

East Asian (EAS)

AF:

0.0125

AC:

AN:

4872

South Asian (SAS)

AF:

0.00182

AC:

AN:

4398

European-Finnish (FIN)

AF:

0.000124

AC:

AN:

8078

Middle Eastern (MID)

AF:

0.00752

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.00165

AC:

107

AN:

65010

Other (OTH)

AF:

0.0192

AC:

AN:

1930

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

127

253

380

506

633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

1017

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 30, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr6-75086648-G-GTATA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over