NM_004370.6:c.1897G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004370.6(COL12A1):c.1897G>A(p.Val633Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000398 in 1,507,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V633F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000058 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 0.285

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

Bethlem myopathy 2
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
Bethlem myopathy 2
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Illumina, Genomics England PanelApp
Ullrich congenital muscular dystrophy 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Bethlem myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ullrich congenital muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

COL12A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.064982414).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004370.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL12A1	NM_004370.6	MANE Select	c.1897G>A	p.Val633Ile	missense	Exon 11 of 66	NP_004361.3
COL12A1	NM_001424113.1		c.1897G>A	p.Val633Ile	missense	Exon 11 of 66	NP_001411042.1
COL12A1	NM_001424114.1		c.1897G>A	p.Val633Ile	missense	Exon 11 of 65	NP_001411043.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.1897G>A	p.Val633Ile	missense	Exon 11 of 66	ENSP00000325146.8	Q99715-1
COL12A1	ENST00000345356.10	TSL:1	c.73+21514G>A		intron	N/A	ENSP00000305147.9	Q99715-2
COL12A1	ENST00000486533.1	TSL:1	n.1003G>A		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes

AF:

0.0000585

AC:

AN:

85522

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000351

Gnomad SAS

AF:

0.000590

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000706

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000610

AC:

AN:

196792

AF XY:

0.0000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000476

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000429

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000387

AC:

AN:

1421560

Hom.:

Cov.:

AF XY:

0.0000439

AC XY:

AN XY:

706028

show subpopulations

African (AFR)

AF:

0.0000639

AC:

AN:

31322

American (AMR)

AF:

0.00

AC:

AN:

37476

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24786

East Asian (EAS)

AF:

0.000256

AC:

AN:

39084

South Asian (SAS)

AF:

0.000150

AC:

AN:

79898

European-Finnish (FIN)

AF:

0.0000192

AC:

AN:

52182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5286

European-Non Finnish (NFE)

AF:

0.0000265

AC:

AN:

1093016

Other (OTH)

AF:

0.0000171

AC:

AN:

58510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000585

AC:

AN:

85522

Hom.:

Cov.:

AF XY:

0.0000738

AC XY:

AN XY:

40630

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23446

American (AMR)

AF:

0.00

AC:

AN:

6282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2198

East Asian (EAS)

AF:

0.000351

AC:

AN:

2846

South Asian (SAS)

AF:

0.000590

AC:

AN:

1694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4676

Middle Eastern (MID)

AF:

0.00

AC:

AN:

206

European-Non Finnish (NFE)

AF:

0.0000706

AC:

AN:

42506

Other (OTH)

AF:

0.00

AC:

AN:

1038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000581

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 (2)

not provided (2)

COL12A1-related disorder (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.064

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.72

M_CAP

Benign

0.040

MetaRNN

Benign

0.065

MetaSVM

Benign

-0.39

MutationAssessor

Benign

1.5

PhyloP100

0.28

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.13

REVEL

Benign

0.28

Sift

Benign

0.40

Sift4G

Uncertain

0.0080

Polyphen

0.28

Vest4

0.060

MutPred

0.43

Gain of sheet (P = 0.0085)

MVP

0.43

MPC

0.097

ClinPred

0.039

GERP RS

4.8

Varity_R

0.026

gMVP

0.23

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over