chr6-75181216-T-TAA

Variant names:

• chr6-75181216-T-TAA
• rs752652515
• NM_004370.6:c.1892-6_1892-5insTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004370.6(COL12A1):​c.1892-6_1892-5insTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000648 in 1,389,228 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: COL12A1 NM_004370.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

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.1892-6_1892-5insTT		splice_region intron	N/A	NP_004361.3
	COL12A1	NM_001424113.1		c.1892-6_1892-5insTT		splice_region intron	N/A	NP_001411042.1
	COL12A1	NM_001424114.1		c.1892-6_1892-5insTT		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.1892-6_1892-5insTT		splice_region intron	N/A	ENSP00000325146.8
	COL12A1	ENST00000345356.10	TSL:1	c.73+21503_73+21504insTT		intron	N/A	ENSP00000305147.9
	COL12A1	ENST00000486533.1	TSL:1	n.998-6_998-5insTT		splice_region intron	N/A

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.00000971 AC: 1 AN: 103032 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000352

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: 0.00000648 AC: 9 AN: 1389228 Hom.: 0 Cov.: 28 AF XY: 0.00000581 AC XY: 4 AN XY: 688832

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

African (AFR) AF: 0.0000331 AC: 1 AN: 30180

American (AMR) AF: 0.00 AC: 0 AN: 33508

Ashkenazi Jewish (ASJ) AF: 0.0000420 AC: 1 AN: 23788

East Asian (EAS) AF: 0.00 AC: 0 AN: 38196

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5214

European-Non Finnish (NFE) AF: 0.00000558 AC: 6 AN: 1074460

Other (OTH) AF: 0.00 AC: 0 AN: 57012

⚠️ 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.

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.5

Splicing

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

Other links and lift over

dbSNP: rs752652515; hg19: chr6-75890932;