6-75086648-GTATATATATATATA-GTATATATATATATATATATA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_004370.6(COL12A1):​c.9182-97_9182-92dupTATATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 288,980 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0052 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: COL12A1 NM_004370.6 intron
• Clinical Significance: Likely 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 6-75086648-G-GTATATA is Benign according to our data. Variant chr6-75086648-G-GTATATA is described in ClinVar as [Likely_benign]. Clinvar id is 1211533.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00519 (735/141654) while in subpopulation AFR AF = 0.0164 (633/38666). AF 95% confidence interval is 0.0153. There are 1 homozygotes in GnomAd4. There are 354 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_9182-92dupTATATA		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_9182-91insTATATA		intron_variant	Intron 65 of 65	1	NM_004370.6	ENSP00000325146.8

Frequencies

GnomAD3 genomes AF: 0.00517 AC: 733 AN: 141658 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00276

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00102

Gnomad SAS AF: 0.00136

Gnomad FIN AF: 0.000124

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000677

Gnomad OTH AF: 0.00364

GnomAD4 exome AF: 0.000210 AC: 31 AN: 147326 Hom.: 0 AF XY: 0.000207 AC XY: 17 AN XY: 82126

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

African (AFR) AF: 0.00118 AC: 3 AN: 2548

American (AMR) AF: 0.000464 AC: 3 AN: 6466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4274

East Asian (EAS) AF: 0.00 AC: 0 AN: 5768

South Asian (SAS) AF: 0.0000780 AC: 1 AN: 12824

European-Finnish (FIN) AF: 0.000104 AC: 2 AN: 19248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 544

European-Non Finnish (NFE) AF: 0.000202 AC: 18 AN: 89132

Other (OTH) AF: 0.000613 AC: 4 AN: 6522

⚠️ 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: 0.00519 AC: 735 AN: 141654 Hom.: 1 Cov.: 0 AF XY: 0.00516 AC XY: 354 AN XY: 68582

African (AFR) AF: 0.0164 AC: 633 AN: 38666

American (AMR) AF: 0.00275 AC: 39 AN: 14164

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

East Asian (EAS) AF: 0.00103 AC: 5 AN: 4874

South Asian (SAS) AF: 0.00136 AC: 6 AN: 4400

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

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

European-Non Finnish (NFE) AF: 0.000677 AC: 44 AN: 65012

Other (OTH) AF: 0.00363 AC: 7 AN: 1930

Alfa AF: 0.000590 Hom.: 1017

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 15, 2019

GeneDx

Significance: Likely 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;