rs374544349

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_004370.6(COL12A1):c.188C>T(p.Thr63Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00005 in 1,600,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

COL12A1
NM_004370.6 missense, splice_region

Scores

Splicing: ADA: 0.2483

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.56

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 Likely_benign. Variant got -1 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=0.18521765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL12A1	NM_004370.6 linkuse as main transcript	c.188C>T	p.Thr63Met	missense_variant, splice_region_variant	3/66	ENST00000322507.13	NP_004361.3	Q99715-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL12A1	ENST00000322507.13 linkuse as main transcript	c.188C>T	p.Thr63Met	missense_variant, splice_region_variant	3/66	1	NM_004370.6	ENSP00000325146.8	Q99715-1
COL12A1	ENST00000345356.10 linkuse as main transcript	c.73+7887C>T		intron_variant		1		ENSP00000305147.9	Q99715-2
COL12A1	ENST00000483888.6 linkuse as main transcript	c.188C>T	p.Thr63Met	missense_variant, splice_region_variant	3/65	5		ENSP00000421216.1	D6RGG3
COL12A1	ENST00000416123.6 linkuse as main transcript	c.188C>T	p.Thr63Met	missense_variant, splice_region_variant	2/63	5		ENSP00000412864.2	Q99715-4

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000530

AC:

AN:

245104

Hom.:

AF XY:

0.0000601

AC XY:

AN XY:

133080

show subpopulations

Gnomad AFR exome

AF:

0.000197

Gnomad AMR exome

AF:

0.0000609

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000337

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000534

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.0000470

AC:

AN:

1448310

Hom.:

Cov.:

AF XY:

0.0000472

AC XY:

AN XY:

720866

show subpopulations

Gnomad4 AFR exome

AF:

0.0000303

Gnomad4 AMR exome

AF:

0.0000456

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000508

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000526

Gnomad4 OTH exome

AF:

0.0000500

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000911

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2024

The c.188C>T (p.T63M) alteration is located in exon 3 (coding exon 2) of the COL12A1 gene. This alteration results from a C to T substitution at nucleotide position 188, causing the threonine (T) at amino acid position 63 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2022

In silico analysis supports that this missense 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 63 of the COL12A1 protein (p.Thr63Met). This variant is present in population databases (rs374544349, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with COL12A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 567843). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.059

T;.;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.3

M;M;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.059

T;T;D

Sift4G

Uncertain

0.014

D;D;D

Polyphen

0.99

D;.;.

Vest4

0.45

MVP

0.60

MPC

0.40

ClinPred

0.13

GERP RS

4.8

Varity_R

0.036

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.25

dbscSNV1_RF

Benign

0.22

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

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