rs35292916

Variant names:

• chr6-75087596-G-A
• rs35292916
• NM_004370.6:c.9162C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-75087596-G-A
• chr6-75087596-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004370.6(COL12A1):​c.9162C>T​(p.Tyr3054Tyr) variant causes a synonymous change. The variant allele was found at a frequency of 0.00326 in 1,613,826 control chromosomes in the GnomAD database, including 237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (209 hom.)
• Consequence: COL12A1 NM_004370.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.53
• Publications: 0 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: Illumina, Ambry Genetics, 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 6-75087596-G-A is Benign according to our data. Variant chr6-75087596-G-A is described in ClinVar as Benign. ClinVar VariationId is 259357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.079 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.9162C>T	p.Tyr3054Tyr	synonymous	Exon 65 of 66	NP_004361.3
	COL12A1	NM_001424113.1		c.9162C>T	p.Tyr3054Tyr	synonymous	Exon 65 of 66	NP_001411042.1
	COL12A1	NM_001424114.1		c.9141C>T	p.Tyr3047Tyr	synonymous	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.9162C>T	p.Tyr3054Tyr	synonymous	Exon 65 of 66	ENSP00000325146.8
	COL12A1	ENST00000345356.10	TSL:1	c.5670C>T	p.Tyr1890Tyr	synonymous	Exon 50 of 51	ENSP00000305147.9
	COL12A1	ENST00000483888.6	TSL:5	c.9150C>T	p.Tyr3050Tyr	synonymous	Exon 65 of 65	ENSP00000421216.1

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 789 AN: 152164 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0440

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0122 AC: 3047 AN: 249148 AF XY: 0.00927

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.0850

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000380

Gnomad OTH exome AF: 0.00810

GnomAD4 exome AF: 0.00305 AC: 4464 AN: 1461544 Hom.: 209 Cov.: 34 AF XY: 0.00267 AC XY: 1938 AN XY: 727088

African (AFR) AF: 0.000867 AC: 29 AN: 33456

American (AMR) AF: 0.0812 AC: 3622 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5752

European-Non Finnish (NFE) AF: 0.000553 AC: 615 AN: 1111878

Other (OTH) AF: 0.00287 AC: 173 AN: 60382

GnomAD4 genome AF: 0.00525 AC: 799 AN: 152282 Hom.: 28 Cov.: 32 AF XY: 0.00532 AC XY: 396 AN XY: 74446

African (AFR) AF: 0.00154 AC: 64 AN: 41548

American (AMR) AF: 0.0446 AC: 683 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68022

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.00172 Hom.: 3

Bravo AF: 0.0105

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	5.3
DANN	Benign	0.58
PhyloP100		6.5
Mutation Taster		=70/30	polymorphism (auto)

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: rs35292916; hg19: chr6-75797312;