rs9447445

Variant names:

• chr6-75105187-T-A
• rs9447445
• NM_004370.6:c.8265+19A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004370.6(COL12A1):​c.8265+19A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0399 in 1,596,606 control chromosomes in the GnomAD database, including 4,848 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2029 hom., cov: 32)
  • Exomes 𝑓: 0.033 (2819 hom.)
• Consequence: COL12A1 NM_004370.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0960
• Publications: 1 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=-0.84).
• BP6: Variant 6-75105187-T-A is Benign according to our data. Variant chr6-75105187-T-A is described in ClinVar as Benign. ClinVar VariationId is 259350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	NM_004370.6	MANE Select	c.8265+19A>T		intron	N/A	NP_004361.3
	COL12A1	NM_001424113.1		c.8265+19A>T		intron	N/A	NP_001411042.1
	COL12A1	NM_001424114.1		c.8244+19A>T		intron	N/A	NP_001411043.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.8265+19A>T		intron	N/A	ENSP00000325146.8
	COL12A1	ENST00000345356.10	TSL:1	c.4773+19A>T		intron	N/A	ENSP00000305147.9
	COL12A1	ENST00000483888.6	TSL:5	c.8265+19A>T		intron	N/A	ENSP00000421216.1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16509 AN: 152052 Hom.: 2016 Cov.: 32

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0835

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.0522

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0923

GnomAD2 exomes AF: 0.0629 AC: 15437 AN: 245468 AF XY: 0.0562

Gnomad AFR exome AF: 0.314

Gnomad AMR exome AF: 0.0741

Gnomad ASJ exome AF: 0.0542

Gnomad EAS exome AF: 0.202

Gnomad FIN exome AF: 0.0159

Gnomad NFE exome AF: 0.0180

Gnomad OTH exome AF: 0.0481

GnomAD4 exome AF: 0.0326 AC: 47117 AN: 1444436 Hom.: 2819 Cov.: 27 AF XY: 0.0321 AC XY: 23124 AN XY: 719582

African (AFR) AF: 0.312 AC: 10289 AN: 32958

American (AMR) AF: 0.0736 AC: 3241 AN: 44008

Ashkenazi Jewish (ASJ) AF: 0.0518 AC: 1340 AN: 25856

East Asian (EAS) AF: 0.169 AC: 6671 AN: 39564

South Asian (SAS) AF: 0.0463 AC: 3945 AN: 85190

European-Finnish (FIN) AF: 0.0163 AC: 866 AN: 53254

Middle Eastern (MID) AF: 0.0491 AC: 281 AN: 5726

European-Non Finnish (NFE) AF: 0.0157 AC: 17283 AN: 1098186

Other (OTH) AF: 0.0536 AC: 3201 AN: 59694

GnomAD4 genome AF: 0.109 AC: 16553 AN: 152170 Hom.: 2029 Cov.: 32 AF XY: 0.108 AC XY: 8054 AN XY: 74404

African (AFR) AF: 0.299 AC: 12377 AN: 41450

American (AMR) AF: 0.0836 AC: 1279 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 143 AN: 3468

East Asian (EAS) AF: 0.187 AC: 967 AN: 5172

South Asian (SAS) AF: 0.0512 AC: 247 AN: 4824

European-Finnish (FIN) AF: 0.0142 AC: 151 AN: 10616

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0172 AC: 1170 AN: 68028

Other (OTH) AF: 0.0928 AC: 196 AN: 2112

Alfa AF: 0.0612 Hom.: 164

Bravo AF: 0.123

Asia WGS AF: 0.132 AC: 458 AN: 3478

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 provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.65
DANN	Benign	0.39
PhyloP100		0.096
Mutation Taster		=100/0	polymorphism (auto)

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: rs9447445; hg19: chr6-75814903;