rs758640189

Positions:

• chr6-75148390-A-C
• chr6-75148390-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_004370.6(COL12A1):​c.4255T>G​(p.Tyr1419Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.53

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 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.4255T>G	p.Tyr1419Asp	missense_variant	22/66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.4255T>G	p.Tyr1419Asp	missense_variant	22/66	1	NM_004370.6	ENSP00000325146.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 1419 of the COL12A1 protein (p.Tyr1419Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL12A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 934440). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL12A1 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;D;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Pathogenic	3.5	.;M;.;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-8.2	.;D;D;D;D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;D;D;.;.
Vest4		0.85
MutPred		0.75		.;Gain of disorder (P = 0.0143);.;Gain of disorder (P = 0.0143);Gain of disorder (P = 0.0143);
MVP		0.91
MPC		0.72
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs758640189; hg19: chr6-75858106;