rs139332405

chr6-75165525-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS1

The NM_004370.6(COL12A1):c.2965G>A(p.Gly989Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,613,676 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G989A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (1 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.04

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL12A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0062682927).
• BP6: Variant 6-75165525-C-T is Benign according to our data. Variant chr6-75165525-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 475854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75165525-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00249 (379/152246) while in subpopulation NFE AF= 0.00228 (155/68012). AF 95% confidence interval is 0.00199. There are 1 homozygotes in gnomad4. There are 244 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.2965G>A	p.Gly989Arg	missense_variant	14/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.2965G>A	p.Gly989Arg	missense_variant	14/66	1	NM_004370.6	P4
COL12A1	ENST00000345356.10	c.74-13043G>A		intron_variant		1
COL12A1	ENST00000483888.6	c.2965G>A	p.Gly989Arg	missense_variant	14/65	5		A1
COL12A1	ENST00000416123.6	c.2965G>A	p.Gly989Arg	missense_variant	13/63	5

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 379 AN: 152128 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0196

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00226 AC: 563 AN: 248684 Hom.: 0 AF XY: 0.00217 AC XY: 293 AN XY: 135002

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00184 AC: 2692 AN: 1461430 Hom.: 1 Cov.: 31 AF XY: 0.00180 AC XY: 1308 AN XY: 727012

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0125

Gnomad4 NFE exome AF: 0.00169

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00249 AC: 379 AN: 152246 Hom.: 1 Cov.: 32 AF XY: 0.00328 AC XY: 244 AN XY: 74452

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0196

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00151 Hom.: 1

Bravo AF: 0.000869

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.00109 AC: 9

ExAC AF: 0.00222 AC: 268

EpiCase AF: 0.00169

EpiControl AF: 0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	COL12A1: BS1, BS2 -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

COL12A1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2020

This variant is classified as 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	0.30
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T;T;T
MetaRNN	Benign	0.0063	T;T;T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.059	T;T;D
Polyphen		1.0	D;.;.
Vest4		0.35
MutPred		0.31		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.79
MPC		0.22
ClinPred		0.036	T
GERP RS		4.7
Varity_R		0.33
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139332405; hg19: chr6-75875241;