rs73749974

Variant names:

• chr6-75151297-C-T
• rs73749974
• NM_004370.6:c.4001-10G>A

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.4001-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00494 in 1,604,996 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (141 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (124 hom.)
• Consequence: COL12A1 NM_004370.6 intron
• Scores: Splicing: ADA: 0.00002180
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.28
• Publications: 1 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 (BayesDel_noAF=-0.92).
• BP6: Variant 6-75151297-C-T is Benign according to our data. Variant chr6-75151297-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0796 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.4001-10G>A		intron	N/A	NP_004361.3
	COL12A1	NM_001424113.1		c.4001-10G>A		intron	N/A	NP_001411042.1
	COL12A1	NM_001424114.1		c.4001-10G>A		intron	N/A	NP_001411043.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.4001-10G>A		intron	N/A	ENSP00000325146.8	Q99715-1
	COL12A1	ENST00000345356.10	TSL:1	c.509-10G>A		intron	N/A	ENSP00000305147.9	Q99715-2
	COL12A1	ENST00000483888.6	TSL:5	c.4001-10G>A		intron	N/A	ENSP00000421216.1	D6RGG3

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3672 AN: 151902 Hom.: 141 Cov.: 32

Gnomad AFR AF: 0.0820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.0226

GnomAD2 exomes AF: 0.00691 AC: 1696 AN: 245534 AF XY: 0.00525

Gnomad AFR exome AF: 0.0854

Gnomad AMR exome AF: 0.00685

Gnomad ASJ exome AF: 0.00192

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.0000472

Gnomad NFE exome AF: 0.000706

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.00292 AC: 4244 AN: 1452976 Hom.: 124 Cov.: 31 AF XY: 0.00257 AC XY: 1855 AN XY: 721918

African (AFR) AF: 0.0852 AC: 2829 AN: 33208

American (AMR) AF: 0.00785 AC: 345 AN: 43958

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 67 AN: 25864

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39546

South Asian (SAS) AF: 0.000530 AC: 45 AN: 84896

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52966

Middle Eastern (MID) AF: 0.00857 AC: 49 AN: 5716

European-Non Finnish (NFE) AF: 0.000476 AC: 527 AN: 1106780

Other (OTH) AF: 0.00628 AC: 377 AN: 60042

GnomAD4 genome AF: 0.0242 AC: 3677 AN: 152020 Hom.: 141 Cov.: 32 AF XY: 0.0236 AC XY: 1755 AN XY: 74308

African (AFR) AF: 0.0819 AC: 3397 AN: 41456

American (AMR) AF: 0.0121 AC: 185 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 67990

Other (OTH) AF: 0.0223 AC: 47 AN: 2106

Alfa AF: 0.0152 Hom.: 38

Bravo AF: 0.0286

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.031
DANN	Benign	0.58
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0060
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: rs73749974; hg19: chr6-75861013;