rs185171880

chr6-75095118-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_004370.6(COL12A1):c.8639A>G(p.His2880Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000297 in 1,614,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.94

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL12A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.025645465).
• BP6: Variant 6-75095118-T-C is Benign according to our data. Variant chr6-75095118-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475905.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000335 (51/152356) while in subpopulation AMR AF= 0.00163 (25/15302). AF 95% confidence interval is 0.00114. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.8639A>G	p.His2880Arg	missense_variant	60/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.8639A>G	p.His2880Arg	missense_variant	60/66	1	NM_004370.6	P4

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000469 AC: 117 AN: 249442 Hom.: 0 AF XY: 0.000488 AC XY: 66 AN XY: 135330

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000309

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000293 AC: 428 AN: 1461810 Hom.: 0 Cov.: 30 AF XY: 0.000275 AC XY: 200 AN XY: 727198

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000255

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74514

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000287 Hom.: 0

Bravo AF: 0.000476

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000262 AC: 1

ESP6500EA AF: 0.000604 AC: 5

ExAC AF: 0.000438 AC: 53

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2022

The c.8639A>G (p.H2880R) alteration is located in exon 60 (coding exon 59) of the COL12A1 gene. This alteration results from a A to G substitution at nucleotide position 8639, causing the histidine (H) at amino acid position 2880 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 14, 2021

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

COL12A1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	18
Dann	Benign	0.81
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.77	T;T;T;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.026	T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.48	N;.;N;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.57	T;.;T;T;T;T
Sift4G	Benign	0.56	T;T;T;T;T;T
Polyphen		0.0010	.;.;B;B;.;.
Vest4		0.15, 0.17, 0.15, 0.16, 0.22
MVP		0.52
MPC		0.58
ClinPred		0.028	T
GERP RS		5.6
Varity_R		0.063
gMVP		0.36

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: rs185171880; hg19: chr6-75804834;