NM_004370.6:c.9083G>A

Variant names:

• chr6-75087675-C-T
• rs41266761
• NM_004370.6:c.9083G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004370.6(COL12A1):​c.9083G>A​(p.Arg3028His) variant causes a missense change. The variant allele was found at a frequency of 0.00566 in 1,610,232 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3028C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0046 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (41 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 5.82
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011844844).
• BP6: Variant 6-75087675-C-T is Benign according to our data. Variant chr6-75087675-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259356.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00461 (702/152248) while in subpopulation NFE AF = 0.0076 (517/68016). AF 95% confidence interval is 0.00706. There are 2 homozygotes in GnomAd4. There are 330 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.9083G>A	p.Arg3028His	missense	Exon 65 of 66	NP_004361.3
	COL12A1	NM_001424113.1		c.9083G>A	p.Arg3028His	missense	Exon 65 of 66	NP_001411042.1
	COL12A1	NM_001424114.1		c.9062G>A	p.Arg3021His	missense	Exon 64 of 65	NP_001411043.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.9083G>A	p.Arg3028His	missense	Exon 65 of 66	ENSP00000325146.8
	COL12A1	ENST00000345356.10	TSL:1	c.5591G>A	p.Arg1864His	missense	Exon 50 of 51	ENSP00000305147.9
	COL12A1	ENST00000483888.6	TSL:5	c.9071G>A	p.Arg3024His	missense	Exon 65 of 65	ENSP00000421216.1

Frequencies

GnomAD3 genomes AF: 0.00462 AC: 703 AN: 152130 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00760

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00407 AC: 996 AN: 244726 AF XY: 0.00413

Gnomad AFR exome AF: 0.00176

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00363

Gnomad NFE exome AF: 0.00701

Gnomad OTH exome AF: 0.00355

GnomAD4 exome AF: 0.00577 AC: 8412 AN: 1457984 Hom.: 41 Cov.: 34 AF XY: 0.00564 AC XY: 4088 AN XY: 725302

African (AFR) AF: 0.00103 AC: 34 AN: 33168

American (AMR) AF: 0.00173 AC: 75 AN: 43468

Ashkenazi Jewish (ASJ) AF: 0.000270 AC: 7 AN: 25944

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39572

South Asian (SAS) AF: 0.000736 AC: 63 AN: 85640

European-Finnish (FIN) AF: 0.00354 AC: 189 AN: 53384

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5742

European-Non Finnish (NFE) AF: 0.00698 AC: 7752 AN: 1110820

Other (OTH) AF: 0.00471 AC: 284 AN: 60246

GnomAD4 genome AF: 0.00461 AC: 702 AN: 152248 Hom.: 2 Cov.: 32 AF XY: 0.00443 AC XY: 330 AN XY: 74440

African (AFR) AF: 0.00173 AC: 72 AN: 41540

American (AMR) AF: 0.00353 AC: 54 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00760 AC: 517 AN: 68016

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00486 Hom.: 15

Bravo AF: 0.00445

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00187 AC: 7

ESP6500EA AF: 0.00709 AC: 58

ExAC AF: 0.00438 AC: 529

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00494

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	1	Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	Ullrich congenital muscular dystrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.014	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.6	L
PhyloP100		5.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.83	N
REVEL	Uncertain	0.53
Sift	Benign	0.90	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.51
MVP		0.79
MPC		1.5
ClinPred		0.020	T
GERP RS		5.8
Varity_R		0.15
gMVP		0.47
Mutation Taster		=87/13	polymorphism

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: rs41266761; hg19: chr6-75797391;