rs970547

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-75087586-C-T
• chr6-75087586-C-A
• chr6-75087586-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004370.6(COL12A1):​c.9172G>A​(p.Gly3058Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.76 in 1,613,022 control chromosomes in the GnomAD database, including 468,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3058N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.73 (40316 hom., cov: 30)
  • Exomes 𝑓: 0.76 (427763 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• 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: 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.371506E-6).
• BP6: Variant 6-75087586-C-T is Benign according to our data. Variant chr6-75087586-C-T is described in ClinVar as Benign. ClinVar VariationId is 259358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	NM_004370.6	MANE Select	c.9172G>A	p.Gly3058Ser	missense	Exon 65 of 66	NP_004361.3
	COL12A1	NM_001424113.1		c.9172G>A	p.Gly3058Ser	missense	Exon 65 of 66	NP_001411042.1
	COL12A1	NM_001424114.1		c.9151G>A	p.Gly3051Ser	missense	Exon 64 of 65	NP_001411043.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.9172G>A	p.Gly3058Ser	missense	Exon 65 of 66	ENSP00000325146.8	Q99715-1
	COL12A1	ENST00000345356.10	TSL:1	c.5680G>A	p.Gly1894Ser	missense	Exon 50 of 51	ENSP00000305147.9	Q99715-2
	COL12A1	ENST00000483888.6	TSL:5	c.9160G>A	p.Gly3054Ser	missense	Exon 65 of 65	ENSP00000421216.1	D6RGG3

Frequencies

GnomAD3 genomes AF: 0.726 AC: 110227 AN: 151856 Hom.: 40303 Cov.: 30

Gnomad AFR AF: 0.656

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.764

Gnomad ASJ AF: 0.762

Gnomad EAS AF: 0.664

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.778

Gnomad OTH AF: 0.742

GnomAD2 exomes AF: 0.747 AC: 185847 AN: 248804 AF XY: 0.741

Gnomad AFR exome AF: 0.657

Gnomad AMR exome AF: 0.837

Gnomad ASJ exome AF: 0.761

Gnomad EAS exome AF: 0.662

Gnomad FIN exome AF: 0.670

Gnomad NFE exome AF: 0.779

Gnomad OTH exome AF: 0.749

GnomAD4 exome AF: 0.764 AC: 1115636 AN: 1461048 Hom.: 427763 Cov.: 56 AF XY: 0.761 AC XY: 552931 AN XY: 726870

African (AFR) AF: 0.647 AC: 21620 AN: 33404

American (AMR) AF: 0.826 AC: 36848 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.767 AC: 20040 AN: 26120

East Asian (EAS) AF: 0.661 AC: 26214 AN: 39640

South Asian (SAS) AF: 0.671 AC: 57797 AN: 86156

European-Finnish (FIN) AF: 0.677 AC: 36133 AN: 53396

Middle Eastern (MID) AF: 0.668 AC: 3828 AN: 5734

European-Non Finnish (NFE) AF: 0.781 AC: 867918 AN: 1111628

Other (OTH) AF: 0.749 AC: 45238 AN: 60364

GnomAD4 genome AF: 0.726 AC: 110286 AN: 151974 Hom.: 40316 Cov.: 30 AF XY: 0.718 AC XY: 53347 AN XY: 74264

African (AFR) AF: 0.656 AC: 27169 AN: 41422

American (AMR) AF: 0.764 AC: 11680 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.762 AC: 2645 AN: 3472

East Asian (EAS) AF: 0.664 AC: 3407 AN: 5130

South Asian (SAS) AF: 0.680 AC: 3276 AN: 4816

European-Finnish (FIN) AF: 0.656 AC: 6927 AN: 10556

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.777 AC: 52851 AN: 67980

Other (OTH) AF: 0.744 AC: 1571 AN: 2112

Alfa AF: 0.765 Hom.: 188659

Bravo AF: 0.734

TwinsUK AF: 0.786 AC: 2914

ALSPAC AF: 0.784 AC: 3020

ESP6500AA AF: 0.659 AC: 2515

ESP6500EA AF: 0.784 AC: 6486

ExAC AF: 0.745 AC: 89988

Asia WGS AF: 0.668 AC: 2327 AN: 3478

EpiCase AF: 0.773

EpiControl AF: 0.771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Bethlem myopathy 2 (1)
-	-	1	Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 (1)
-	-	1	not provided (1)
-	-	1	Ullrich congenital muscular dystrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0000034	T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	2.0	M
PhyloP100		7.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.023	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.44
MPC		1.4
ClinPred		0.016	T
GERP RS		5.8
Varity_R		0.26
gMVP		0.76
Mutation Taster		=83/17	polymorphism (auto)

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

Other links and lift over

dbSNP: rs970547; hg19: chr6-75797302; COSMIC: COSV59392062; COSMIC: COSV59392062;