6-75086648-GTATATATATATATA-GTATATATATATATATATA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_004370.6(COL12A1):​c.9182-95_9182-92dupTATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 288,876 control chromosomes in the GnomAD database, including 101 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.023 (101 hom., cov: 0)
  • Exomes 𝑓: 0.00096 (0 hom.)
• Consequence: COL12A1 NM_004370.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 6-75086648-G-GTATA is Benign according to our data. Variant chr6-75086648-G-GTATA is described in ClinVar as [Benign]. Clinvar id is 1228153.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.9182-95_9182-92dupTATA		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.9182-92_9182-91insTATA		intron_variant	Intron 65 of 65	1	NM_004370.6	ENSP00000325146.8

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3296 AN: 141596 Hom.: 99 Cov.: 0

Gnomad AFR AF: 0.0753

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0127

Gnomad SAS AF: 0.00181

Gnomad FIN AF: 0.000124

Gnomad MID AF: 0.00694

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.0182

GnomAD4 exome AF: 0.000957 AC: 141 AN: 147286 Hom.: 0 AF XY: 0.000974 AC XY: 80 AN XY: 82110

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

African (AFR) AF: 0.0106 AC: 27 AN: 2546

American (AMR) AF: 0.00155 AC: 10 AN: 6466

Ashkenazi Jewish (ASJ) AF: 0.000234 AC: 1 AN: 4270

East Asian (EAS) AF: 0.000868 AC: 5 AN: 5762

South Asian (SAS) AF: 0.00101 AC: 13 AN: 12822

European-Finnish (FIN) AF: 0.000208 AC: 4 AN: 19244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 542

European-Non Finnish (NFE) AF: 0.000763 AC: 68 AN: 89114

Other (OTH) AF: 0.00199 AC: 13 AN: 6520

⚠️ 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: 0.0233 AC: 3303 AN: 141590 Hom.: 101 Cov.: 0 AF XY: 0.0236 AC XY: 1617 AN XY: 68548

African (AFR) AF: 0.0754 AC: 2910 AN: 38610

American (AMR) AF: 0.0125 AC: 177 AN: 14162

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

East Asian (EAS) AF: 0.0125 AC: 61 AN: 4872

South Asian (SAS) AF: 0.00182 AC: 8 AN: 4398

European-Finnish (FIN) AF: 0.000124 AC: 1 AN: 8078

Middle Eastern (MID) AF: 0.00752 AC: 2 AN: 266

European-Non Finnish (NFE) AF: 0.00165 AC: 107 AN: 65010

Other (OTH) AF: 0.0192 AC: 37 AN: 1930

Alfa AF: 0.00 Hom.: 1017

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 30, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
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;