chr6-75087586-C-A

Variant names:

• chr6-75087586-C-A
• rs970547
• NM_004370.6:c.9172G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004370.6(COL12A1):​c.9172G>T​(p.Gly3058Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3058S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• Publications: 69 publications found

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: Labcorp Genetics (formerly Invitae), Orphanet
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.9172G>T	p.Gly3058Cys	missense_variant	Exon 65 of 66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.9172G>T	p.Gly3058Cys	missense_variant	Exon 65 of 66	1	NM_004370.6	ENSP00000325146.8

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 56

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;T;D;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	2.0	.;.;M;.;.;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.9	D;.;D;D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D;.;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D;D
Polyphen		1.0	.;.;D;D;.;.
Vest4		0.63, 0.67, 0.64, 0.65, 0.56
MutPred		0.55		.;.;Loss of phosphorylation at S3062 (P = 0.0769);.;.;.;
MVP		0.76
MPC		1.4
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.55
gMVP		0.89
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs970547; hg19: chr6-75797302;