6-75086648-G-GTA

Variant names:

• chr6-75086648-G-GTA
• rs61611291
• NM_004370.6:c.9182-93_9182-92dupTA

Variant summary

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

The NM_004370.6(COL12A1):​c.9182-93_9182-92dupTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0614 in 288,312 control chromosomes in the GnomAD database, including 1,321 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1320 hom., cov: 0)
  • Exomes 𝑓: 0.018 (1 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-GTA is Benign according to our data. Variant chr6-75086648-G-GTA is described in ClinVar as [Benign]. Clinvar id is 1264862.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.9182-93_9182-92dupTA		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_9182-91insTA		intron_variant	Intron 65 of 65	1	NM_004370.6	ENSP00000325146.8

Frequencies

GnomAD3 genomes AF: 0.106 AC: 15063 AN: 141482 Hom.: 1322 Cov.: 0

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.0675

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.0235

Gnomad SAS AF: 0.0493

Gnomad FIN AF: 0.0354

Gnomad MID AF: 0.0590

Gnomad NFE AF: 0.0524

Gnomad OTH AF: 0.0796

GnomAD4 exome AF: 0.0179 AC: 2631 AN: 146836 Hom.: 1 AF XY: 0.0174 AC XY: 1425 AN XY: 81822

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

African (AFR) AF: 0.0567 AC: 144 AN: 2538

American (AMR) AF: 0.00945 AC: 61 AN: 6456

Ashkenazi Jewish (ASJ) AF: 0.0120 AC: 51 AN: 4260

East Asian (EAS) AF: 0.00573 AC: 33 AN: 5756

South Asian (SAS) AF: 0.00921 AC: 118 AN: 12806

European-Finnish (FIN) AF: 0.0241 AC: 460 AN: 19114

Middle Eastern (MID) AF: 0.00735 AC: 4 AN: 544

European-Non Finnish (NFE) AF: 0.0185 AC: 1648 AN: 88860

Other (OTH) AF: 0.0172 AC: 112 AN: 6502

⚠️ 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: 0.106 AC: 15060 AN: 141476 Hom.: 1320 Cov.: 0 AF XY: 0.104 AC XY: 7118 AN XY: 68500

African (AFR) AF: 0.251 AC: 9668 AN: 38574

American (AMR) AF: 0.0675 AC: 956 AN: 14154

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 101 AN: 3366

East Asian (EAS) AF: 0.0236 AC: 115 AN: 4866

South Asian (SAS) AF: 0.0489 AC: 215 AN: 4394

European-Finnish (FIN) AF: 0.0354 AC: 286 AN: 8068

Middle Eastern (MID) AF: 0.0526 AC: 14 AN: 266

European-Non Finnish (NFE) AF: 0.0524 AC: 3405 AN: 64960

Other (OTH) AF: 0.0793 AC: 153 AN: 1930

Alfa AF: 0.0348 Hom.: 1017

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 10, 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 (auto)

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;