rs1554182853

Variant names:

• chr6-75151285-T-A
• rs1554182853
• NM_004370.6:c.4003A>T

Your query was ambiguous. Multiple possible variants found:

• chr6-75151285-T-A
• chr6-75151285-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001424113.1(COL12A1):​c.4003A>T​(p.Ile1335Phe) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL12A1 NM_001424113.1 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81
• 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: 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001424113.1. 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.4003A>T	p.Ile1335Phe	missense splice_region	Exon 21 of 66	NP_004361.3
	COL12A1	NM_001424113.1		c.4003A>T	p.Ile1335Phe	missense splice_region	Exon 21 of 66	NP_001411042.1
	COL12A1	NM_001424114.1		c.4003A>T	p.Ile1335Phe	missense splice_region	Exon 21 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.4003A>T	p.Ile1335Phe	missense splice_region	Exon 21 of 66	ENSP00000325146.8
	COL12A1	ENST00000345356.10	TSL:1	c.511A>T	p.Ile171Phe	missense splice_region	Exon 6 of 51	ENSP00000305147.9
	COL12A1	ENST00000483888.6	TSL:5	c.4003A>T	p.Ile1335Phe	missense splice_region	Exon 21 of 65	ENSP00000421216.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.77
Sift	Benign	0.11	T
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.57
MVP		0.66
MPC		0.72
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.39
gMVP		0.95
Mutation Taster		=60/40	polymorphism

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: rs1554182853; hg19: chr6-75861001;