rs139332405

Positions:

chr6-75165525-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS1

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.04

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL12A1. . Gene score misZ 2.106 (greater than the threshold 3.09). Trascript score misZ 3.5535 (greater than threshold 3.09). GenCC has associacion of gene with Bethlem myopathy, Bethlem myopathy 2, Ullrich congenital muscular dystrophy 2, Ullrich congenital muscular dystrophy.

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. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6 linkuse as main transcript	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 linkuse as main transcript	c.2965G>A	p.Gly989Arg	missense_variant	14/66	1	NM_004370.6	P4	Q99715-1
COL12A1	ENST00000345356.10 linkuse as main transcript	c.74-13043G>A		intron_variant		1			Q99715-2
COL12A1	ENST00000483888.6 linkuse as main transcript	c.2965G>A	p.Gly989Arg	missense_variant	14/65	5		A1
COL12A1	ENST00000416123.6 linkuse as main transcript	c.2965G>A	p.Gly989Arg	missense_variant	13/63	5			Q99715-4

Frequencies

GnomAD3 genomes

AF:

0.00249

AC:

379

AN:

152128

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00217

AC XY:

293

AN XY:

135002

show subpopulations

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.:

Cov.:

AF XY:

0.00180

AC XY:

1308

AN XY:

727012

show subpopulations

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.:

Cov.:

AF XY:

0.00328

AC XY:

244

AN XY:

74452

show subpopulations

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.:

Bravo

AF:

0.000869

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000258

AC:

ESP6500EA

AF:

0.00109

AC:

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

LINK: link

Submissions by phenotype

not provided

Benign:2

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

COL12A1-related disorder

Benign:1

Benign, no assertion criteria provided

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). -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;.;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

T;T;T

MetaRNN

Benign

0.0063

T;T;T

MetaSVM

Uncertain

0.63

MutationAssessor

Uncertain

2.8

M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.47

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over