rs759294983

Variant names:

• chr6-75154514-T-A
• rs759294983
• NM_004370.6:c.3467A>T

Your query was ambiguous. Multiple possible variants found:

• chr6-75154514-T-A
• chr6-75154514-T-C

Variant summary

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

The NM_004370.6(COL12A1):​c.3467A>T​(p.Asn1156Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1156H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.3467A>T	p.Asn1156Ile	missense_variant	Exon 17 of 66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.3467A>T	p.Asn1156Ile	missense_variant	Exon 17 of 66	1	NM_004370.6	ENSP00000325146.8
COL12A1	ENST00000345356.10	c.74-2032A>T		intron_variant	Intron 2 of 50	1		ENSP00000305147.9
COL12A1	ENST00000483888.6	c.3467A>T	p.Asn1156Ile	missense_variant	Exon 17 of 65	5		ENSP00000421216.1
COL12A1	ENST00000416123.6	c.3467A>T	p.Asn1156Ile	missense_variant	Exon 16 of 63	5		ENSP00000412864.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Uncertain:1

Feb 12, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with COL12A1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with isoleucine at codon 1156 of the COL12A1 protein (p.Asn1156Ile). The asparagine residue is moderately conserved and there is a large physicochemical difference between asparagine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.7	L;L;.
PhyloP100		1.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.045	D;D;D
Sift4G	Uncertain	0.029	D;D;D
Polyphen		0.98	D;.;.
Vest4		0.79
MutPred		0.46		Loss of catalytic residue at N1156 (P = 0.0055);Loss of catalytic residue at N1156 (P = 0.0055);Loss of catalytic residue at N1156 (P = 0.0055);
MVP		0.63
MPC		0.47
ClinPred		0.91	D
GERP RS		5.3
Varity_R		0.28
gMVP		0.72
Mutation Taster		=65/35	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: rs759294983; hg19: chr6-75864230;