6-75134848-A-G

Position:

chr6-75134848-A-G

Variant summary

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

The NM_004370.6(COL12A1):c.5402T>C(p.Ile1801Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000247 in 1,609,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. I1801M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 6.92

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=0.007816404).

BP6

Variant 6-75134848-A-G is Benign according to our data. Variant chr6-75134848-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 475875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00135 (205/152268) while in subpopulation AFR AF= 0.00445 (185/41562). AF 95% confidence interval is 0.00393. There are 0 homozygotes in gnomad4. There are 95 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.5402T>C	p.Ile1801Thr	missense_variant	32/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13 linkuse as main transcript	c.5402T>C	p.Ile1801Thr	missense_variant	32/66	1	NM_004370.6	P4	Q99715-1

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

205

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00446

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000317

AC:

AN:

249212

Hom.:

AF XY:

0.000222

AC XY:

AN XY:

135206

show subpopulations

Gnomad AFR exome

AF:

0.00433

Gnomad AMR exome

AF:

0.000319

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:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000132

AC:

192

AN:

1457614

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

725142

show subpopulations

Gnomad4 AFR exome

AF:

0.00443

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000361

Gnomad4 OTH exome

AF:

0.000299

GnomAD4 genome

AF:

0.00135

AC:

205

AN:

152268

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00445

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000221

Hom.:

Bravo

AF:

0.00161

ESP6500AA

AF:

0.00355

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000422

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

COL12A1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 03, 2019

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). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2020

- -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.018

T;T;.;.;.

Eigen

Benign

0.039

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;D;D

M_CAP

Benign

0.0092

MetaRNN

Benign

0.0078

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.85

.;L;.;L;.

MutationTaster

Benign

0.73

N;N;N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.4

.;N;N;N;N

REVEL

Benign

0.11

Sift

Uncertain

0.0060

.;D;T;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D

Polyphen

0.22, 0.026

.;B;B;.;.

Vest4

0.27

MVP

0.25

MPC

0.21

ClinPred

0.039

GERP RS

5.9

Varity_R

0.16

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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