6-75086648-GTATATATATATATA-GTATATATA

Variant names:

• chr6-75086648-GTATATA-G
• rs61611291
• NM_004370.6:c.9182-97_9182-92delTATATA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_004370.6(COL12A1):​c.9182-97_9182-92delTATATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 287,118 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: 𝑓 0.00020 (0 hom., cov: 0)
  • Exomes 𝑓: 0.011 (0 hom.)
• Consequence: COL12A1 NM_004370.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.440
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000198 (28/141650) while in subpopulation SAS AF = 0.000909 (4/4400). AF 95% confidence interval is 0.00031. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.9182-97_9182-92delTATATA		intron_variant	Intron 65 of 65	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.9182-97_9182-92delTATATA		intron_variant	Intron 65 of 65	1	NM_004370.6	ENSP00000325146.8

Frequencies

GnomAD3 genomes AF: 0.000198 AC: 28 AN: 141654 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000141

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000204

Gnomad SAS AF: 0.000904

Gnomad FIN AF: 0.000124

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000123

Gnomad OTH AF: 0.00104

GnomAD4 exome AF: 0.0108 AC: 1569 AN: 145468 Hom.: 0 AF XY: 0.0109 AC XY: 884 AN XY: 81124

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

African (AFR) AF: 0.00630 AC: 16 AN: 2540

American (AMR) AF: 0.00654 AC: 42 AN: 6424

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 73 AN: 4220

East Asian (EAS) AF: 0.0126 AC: 72 AN: 5708

South Asian (SAS) AF: 0.00732 AC: 93 AN: 12712

European-Finnish (FIN) AF: 0.00482 AC: 91 AN: 18896

Middle Eastern (MID) AF: 0.0150 AC: 8 AN: 532

European-Non Finnish (NFE) AF: 0.0126 AC: 1111 AN: 87994

Other (OTH) AF: 0.00978 AC: 63 AN: 6442

⚠️ 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.

GnomAD4 genome AF: 0.000198 AC: 28 AN: 141650 Hom.: 0 Cov.: 0 AF XY: 0.000219 AC XY: 15 AN XY: 68578

African (AFR) AF: 0.000259 AC: 10 AN: 38680

American (AMR) AF: 0.000141 AC: 2 AN: 14164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3366

East Asian (EAS) AF: 0.000205 AC: 1 AN: 4874

South Asian (SAS) AF: 0.000909 AC: 4 AN: 4400

European-Finnish (FIN) AF: 0.000124 AC: 1 AN: 8072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.000123 AC: 8 AN: 65000

Other (OTH) AF: 0.00104 AC: 2 AN: 1930

Alfa AF: 0.00 Hom.: 1017

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.44
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs61611291; hg19: chr6-75796364;