6-75181216-TTAA-T

Variant names:

• chr6-75181216-TTAA-T
• rs199713791
• NM_004370.6:c.1892-8_1892-6delTTA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004370.6(COL12A1):​c.1892-8_1892-6delTTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,408,090 control chromosomes in the GnomAD database, including 63 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (38 hom., cov: 0)
  • Exomes 𝑓: 0.0013 (25 hom.)
• Consequence: COL12A1 NM_004370.6 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.687
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 6-75181216-TTAA-T is Benign according to our data. Variant chr6-75181216-TTAA-T is described in ClinVar as Benign. ClinVar VariationId is 475848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004370.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	NM_004370.6	MANE Select	c.1892-8_1892-6delTTA		splice_region intron	N/A	NP_004361.3
	COL12A1	NM_001424113.1		c.1892-8_1892-6delTTA		splice_region intron	N/A	NP_001411042.1
	COL12A1	NM_001424114.1		c.1892-8_1892-6delTTA		splice_region intron	N/A	NP_001411043.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.1892-8_1892-6delTTA		splice_region intron	N/A	ENSP00000325146.8
	COL12A1	ENST00000345356.10	TSL:1	c.73+21501_73+21503delTTA		intron	N/A	ENSP00000305147.9
	COL12A1	ENST00000486533.1	TSL:1	n.998-8_998-6delTTA		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.105 AC: 1953 AN: 18578 Hom.: 38 Cov.: 0

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0679

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0263

Gnomad NFE AF: 0.00298

Gnomad OTH AF: 0.0365

GnomAD2 exomes AF: 0.00752 AC: 775 AN: 103032 AF XY: 0.00583

Gnomad AFR exome AF: 0.0711

Gnomad AMR exome AF: 0.00563

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.00252

GnomAD4 exome AF: 0.00129 AC: 1796 AN: 1389488 Hom.: 25 AF XY: 0.00109 AC XY: 750 AN XY: 688978

African (AFR) AF: 0.0460 AC: 1388 AN: 30156

American (AMR) AF: 0.00289 AC: 97 AN: 33516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23804

East Asian (EAS) AF: 0.00 AC: 0 AN: 38204

South Asian (SAS) AF: 0.000144 AC: 11 AN: 76272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50640

Middle Eastern (MID) AF: 0.00249 AC: 13 AN: 5214

European-Non Finnish (NFE) AF: 0.0000912 AC: 98 AN: 1074646

Other (OTH) AF: 0.00331 AC: 189 AN: 57036

GnomAD4 genome AF: 0.105 AC: 1957 AN: 18602 Hom.: 38 Cov.: 0 AF XY: 0.103 AC XY: 935 AN XY: 9094

African (AFR) AF: 0.146 AC: 1870 AN: 12798

American (AMR) AF: 0.0678 AC: 69 AN: 1018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 128

East Asian (EAS) AF: 0.00 AC: 0 AN: 238

South Asian (SAS) AF: 0.00 AC: 0 AN: 100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 680

Middle Eastern (MID) AF: 0.0278 AC: 1 AN: 36

European-Non Finnish (NFE) AF: 0.00297 AC: 10 AN: 3364

Other (OTH) AF: 0.0357 AC: 7 AN: 196

Alfa AF: 0.0135 Hom.: 4

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Sep 30, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.69
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: rs199713791; hg19: chr6-75890932;