rs875989819

Variant names:

• chr6-75113601-C-T
• rs875989819
• NM_004370.6:c.7840+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PS3 PP5_Moderate

The NM_004370.6(COL12A1):​c.7840+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000076 in 1,448,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV002230776: Studies have shown that disruption of this splice site results in exon skipping and introduces a premature termination codon (PMID:24334604).".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: COL12A1 NM_004370.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.57
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Pathogenic. The variant received 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002230776: Studies have shown that disruption of this splice site results in exon skipping and introduces a premature termination codon (PMID: 24334604).
• PP5: Variant 6-75113601-C-T is Pathogenic according to our data. Variant chr6-75113601-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 204294.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	NM_004370.6	MANE Select	c.7840+1G>A		splice_donor intron	N/A	NP_004361.3
	COL12A1	NM_001424113.1		c.7840+1G>A		splice_donor intron	N/A	NP_001411042.1
	COL12A1	NM_001424114.1		c.7819+1G>A		splice_donor intron	N/A	NP_001411043.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.7840+1G>A		splice_donor intron	N/A	ENSP00000325146.8	Q99715-1
	COL12A1	ENST00000345356.10	TSL:1	c.4348+1G>A		splice_donor intron	N/A	ENSP00000305147.9	Q99715-2
	COL12A1	ENST00000483888.6	TSL:5	c.7840+1G>A		splice_donor intron	N/A	ENSP00000421216.1	D6RGG3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246260 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000760 AC: 11 AN: 1448074 Hom.: 0 Cov.: 30 AF XY: 0.00000417 AC XY: 3 AN XY: 720050

African (AFR) AF: 0.00 AC: 0 AN: 33142

American (AMR) AF: 0.0000227 AC: 1 AN: 44058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25662

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39508

South Asian (SAS) AF: 0.00 AC: 0 AN: 83406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52696

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5700

European-Non Finnish (NFE) AF: 0.00000634 AC: 7 AN: 1104236

Other (OTH) AF: 0.00 AC: 0 AN: 59666

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 (1)
1	-	-	Ullrich congenital muscular dystrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.6
GERP RS		6.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: 1

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

Other links and lift over

dbSNP: rs875989819; hg19: chr6-75823317;