chr6-75152357-T-G

Variant names:

• chr6-75152357-T-G
• rs1449618151
• NM_004370.6:c.3691A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004370.6(COL12A1):​c.3691A>C​(p.Ile1231Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. I1231V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.84
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40941808).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	NM_004370.6	MANE Select	c.3691A>C	p.Ile1231Leu	missense	Exon 18 of 66	NP_004361.3
	COL12A1	NM_001424113.1		c.3691A>C	p.Ile1231Leu	missense	Exon 18 of 66	NP_001411042.1
	COL12A1	NM_001424114.1		c.3691A>C	p.Ile1231Leu	missense	Exon 18 of 65	NP_001411043.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.3691A>C	p.Ile1231Leu	missense	Exon 18 of 66	ENSP00000325146.8
	COL12A1	ENST00000345356.10	TSL:1	c.199A>C	p.Ile67Leu	missense	Exon 3 of 51	ENSP00000305147.9
	COL12A1	ENST00000483888.6	TSL:5	c.3691A>C	p.Ile1231Leu	missense	Exon 18 of 65	ENSP00000421216.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.015	B
Vest4		0.66
MutPred		0.65		Loss of catalytic residue at P1233 (P = 0.0298)
MVP		0.74
MPC		0.12
ClinPred		0.91	D
GERP RS		5.7
PromoterAI		0.038	Neutral
Varity_R		0.39
gMVP		0.73
Mutation Taster		=82/18	polymorphism

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: rs1449618151; hg19: chr6-75862073;