rs200315815

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS1

The NM_004370.6(COL12A1):c.1897G>T(p.Val633Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,507,156 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V633I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.285

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 -8 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=0.008966267).

BP6

Variant 6-75181206-C-A is Benign according to our data. Variant chr6-75181206-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475849.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00251 (215/85602) while in subpopulation AFR AF= 0.00871 (205/23532). AF 95% confidence interval is 0.00773. There are 0 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 31. 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.1897G>T	p.Val633Phe	missense_variant	11/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13 linkuse as main transcript	c.1897G>T	p.Val633Phe	missense_variant	11/66	1	NM_004370.6	P4	Q99715-1

Frequencies

GnomAD3 genomes

AF:

0.00251

AC:

215

AN:

85518

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00874

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00143

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000963

GnomAD3 exomes

AF:

0.000447

AC:

AN:

196792

Hom.:

AF XY:

0.000295

AC XY:

AN XY:

108634

show subpopulations

Gnomad AFR exome

AF:

0.00474

Gnomad AMR exome

AF:

0.000841

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000321

Gnomad OTH exome

AF:

0.000453

GnomAD4 exome

AF:

0.000146

AC:

207

AN:

1421554

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

706022

show subpopulations

Gnomad4 AFR exome

AF:

0.00501

Gnomad4 AMR exome

AF:

0.000694

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000823

Gnomad4 OTH exome

AF:

0.000239

GnomAD4 genome

AF:

0.00251

AC:

215

AN:

85602

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

100

AN XY:

40718

show subpopulations

Gnomad4 AFR

AF:

0.00871

Gnomad4 AMR

AF:

0.00143

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000260

Hom.:

Bravo

AF:

0.00178

ESP6500AA

AF:

0.00354

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000506

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 12, 2021	- -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.055

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.;.

Eigen

Benign

-0.061

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.0090

T;T;T

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.0

M;M;.

MutationTaster

Benign

0.99

D;D;D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.1

N;N;N

REVEL

Uncertain

0.44

Sift

Benign

0.040

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

0.98

D;.;P

Vest4

0.19

MVP

0.58

MPC

0.22

ClinPred

0.011

GERP RS

4.8

Varity_R

0.088

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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