chr6-75091544-A-T

Variant names:

• chr6-75091544-A-T
• rs79461746
• NM_004370.6:c.8650-19T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004370.6(COL12A1):​c.8650-19T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,607,370 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (43 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (45 hom.)
• Consequence: COL12A1 NM_004370.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.88
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-75091544-A-T is Benign according to our data. Variant chr6-75091544-A-T is described in ClinVar as Benign. ClinVar VariationId is 259354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0135 (2052/152334) while in subpopulation AFR AF = 0.0446 (1852/41568). AF 95% confidence interval is 0.0429. There are 43 homozygotes in GnomAd4. There are 968 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004370.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	NM_004370.6	MANE Select	c.8650-19T>A		intron	N/A	NP_004361.3
	COL12A1	NM_001424113.1		c.8650-19T>A		intron	N/A	NP_001411042.1
	COL12A1	NM_001424114.1		c.8629-19T>A		intron	N/A	NP_001411043.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.8650-19T>A		intron	N/A	ENSP00000325146.8
	COL12A1	ENST00000345356.10	TSL:1	c.5158-19T>A		intron	N/A	ENSP00000305147.9
	COL12A1	ENST00000483888.6	TSL:5	c.8638-19T>A		intron	N/A	ENSP00000421216.1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2048 AN: 152216 Hom.: 43 Cov.: 33

Gnomad AFR AF: 0.0445

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00407 AC: 1010 AN: 248290 AF XY: 0.00309

Gnomad AFR exome AF: 0.0486

Gnomad AMR exome AF: 0.00441

Gnomad ASJ exome AF: 0.000796

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000473

Gnomad NFE exome AF: 0.000621

Gnomad OTH exome AF: 0.00464

GnomAD4 exome AF: 0.00169 AC: 2461 AN: 1455036 Hom.: 45 Cov.: 29 AF XY: 0.00146 AC XY: 1055 AN XY: 724208

African (AFR) AF: 0.0436 AC: 1453 AN: 33310

American (AMR) AF: 0.00447 AC: 200 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 32 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86046

European-Finnish (FIN) AF: 0.0000378 AC: 2 AN: 52916

Middle Eastern (MID) AF: 0.00441 AC: 19 AN: 4304

European-Non Finnish (NFE) AF: 0.000431 AC: 478 AN: 1108030

Other (OTH) AF: 0.00455 AC: 273 AN: 60056

GnomAD4 genome AF: 0.0135 AC: 2052 AN: 152334 Hom.: 43 Cov.: 33 AF XY: 0.0130 AC XY: 968 AN XY: 74490

African (AFR) AF: 0.0446 AC: 1852 AN: 41568

American (AMR) AF: 0.00850 AC: 130 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68030

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.0152

Asia WGS AF: 0.00376 AC: 13 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.0
DANN	Benign	0.74
PhyloP100		2.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs79461746; hg19: chr6-75801260;