rs41266761

chr6-75087675-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 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:10
• Conservation: PhyloP100: 5.82

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL12A1
• 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 id is 259356.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=4, Uncertain_significance=1}. Variant chr6-75087675-C-T is described in Lovd as [Likely_benign]. Variant chr6-75087675-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.9083G>A	p.Arg3028His	missense_variant	65/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.9083G>A	p.Arg3028His	missense_variant	65/66	1	NM_004370.6	P4

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

GnomAD3 exomes AF: 0.00407 AC: 996 AN: 244726 Hom.: 9 AF XY: 0.00413 AC XY: 549 AN XY: 132950

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 SAS exome AF: 0.000804

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

Gnomad4 AFR exome AF: 0.00103

Gnomad4 AMR exome AF: 0.00173

Gnomad4 ASJ exome AF: 0.000270

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000736

Gnomad4 FIN exome AF: 0.00354

Gnomad4 NFE exome AF: 0.00698

Gnomad4 OTH exome AF: 0.00471

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

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00760

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00613 Hom.: 8

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	COL12A1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 29, 2020	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The c.9083G>A (p.R3028H) alteration is located in exon 65 (coding exon 64) of the COL12A1 gene. This alteration results from a G to A substitution at nucleotide position 9083, causing the arginine (R) at amino acid position 3028 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Ullrich congenital muscular dystrophy 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.012	T;T;T;T;T;T
MetaSVM	Uncertain	0.78	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.83	N;.;N;N;N;N
REVEL	Uncertain	0.53
Sift	Benign	0.90	T;.;T;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T;T
Polyphen		1.0	.;.;D;D;.;.
Vest4		0.51, 0.55, 0.56, 0.63, 0.52
MVP		0.79
MPC		1.5
ClinPred		0.020	T
GERP RS		5.8
Varity_R		0.15
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs41266761; hg19: chr6-75797391;