6-75086648-GTATATATATATATA-GTATATATATA

Variant names:

• chr6-75086648-GTATA-G
• rs61611291
• NM_004370.6:c.9182-95_9182-92delTATA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_004370.6(COL12A1):​c.9182-95_9182-92delTATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0696 in 283,588 control chromosomes in the GnomAD database, including 9 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0070 (6 hom., cov: 0)
  • Exomes 𝑓: 0.13 (3 hom.)
• Consequence: COL12A1 NM_004370.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00701 (991/141326) while in subpopulation SAS AF = 0.0134 (59/4394). AF 95% confidence interval is 0.0107. There are 6 homozygotes in GnomAd4. There are 488 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.9182-95_9182-92delTATA		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.9182-95_9182-92delTATA		intron_variant	Intron 65 of 65	1	NM_004370.6	ENSP00000325146.8

Frequencies

GnomAD3 genomes AF: 0.00698 AC: 987 AN: 141332 Hom.: 6 Cov.: 0

Gnomad AFR AF: 0.00795

Gnomad AMI AF: 0.0134

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00416

Gnomad EAS AF: 0.00287

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.00874

Gnomad MID AF: 0.00699

Gnomad NFE AF: 0.00628

Gnomad OTH AF: 0.00886

GnomAD4 exome AF: 0.132 AC: 18754 AN: 142262 Hom.: 3 AF XY: 0.133 AC XY: 10544 AN XY: 79306

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

African (AFR) AF: 0.0392 AC: 99 AN: 2528

American (AMR) AF: 0.0697 AC: 445 AN: 6388

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 652 AN: 4170

East Asian (EAS) AF: 0.120 AC: 681 AN: 5666

South Asian (SAS) AF: 0.0774 AC: 981 AN: 12668

European-Finnish (FIN) AF: 0.154 AC: 2678 AN: 17436

Middle Eastern (MID) AF: 0.160 AC: 85 AN: 532

European-Non Finnish (NFE) AF: 0.142 AC: 12307 AN: 86512

Other (OTH) AF: 0.130 AC: 826 AN: 6362

⚠️ 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: 0.00701 AC: 991 AN: 141326 Hom.: 6 Cov.: 0 AF XY: 0.00714 AC XY: 488 AN XY: 68382

African (AFR) AF: 0.00804 AC: 311 AN: 38678

American (AMR) AF: 0.00601 AC: 85 AN: 14134

Ashkenazi Jewish (ASJ) AF: 0.00416 AC: 14 AN: 3362

East Asian (EAS) AF: 0.00288 AC: 14 AN: 4862

South Asian (SAS) AF: 0.0134 AC: 59 AN: 4394

European-Finnish (FIN) AF: 0.00874 AC: 70 AN: 8008

Middle Eastern (MID) AF: 0.00758 AC: 2 AN: 264

European-Non Finnish (NFE) AF: 0.00628 AC: 407 AN: 64800

Other (OTH) AF: 0.00883 AC: 17 AN: 1926

Alfa AF: 0.00865 Hom.: 1017

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
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: rs61611291; hg19: chr6-75796364;