chr6-75154514-T-A

Position:

• chr6-75154514-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL12A1. . Gene score misZ 2.106 (greater than the threshold 3.09). Trascript score misZ 3.5535 (greater than threshold 3.09). GenCC has associacion of gene with Bethlem myopathy, Bethlem myopathy 2, Ullrich congenital muscular dystrophy 2, Ullrich congenital muscular dystrophy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.3467A>T	p.Asn1156Ile	missense_variant	17/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.3467A>T	p.Asn1156Ile	missense_variant	17/66	1	NM_004370.6	P4
COL12A1	ENST00000345356.10	c.74-2032A>T		intron_variant		1
COL12A1	ENST00000483888.6	c.3467A>T	p.Asn1156Ile	missense_variant	17/65	5		A1
COL12A1	ENST00000416123.6	c.3467A>T	p.Asn1156Ile	missense_variant	16/63	5

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 12, 2018

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;.
MutationTaster	Benign	0.73	D;D;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs759294983; hg19: chr6-75864230;