rs200317239

Positions:

• chr6-75134848-A-C
• chr6-75134848-A-G

Variant summary

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

The NM_004370.6(COL12A1):​c.5402T>G​(p.Ile1801Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,614 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I1801T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.92

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 where missense usually causes diseases, COL12A1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.5402T>G	p.Ile1801Arg	missense_variant	32/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.5402T>G	p.Ile1801Arg	missense_variant	32/66	1	NM_004370.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249212 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457614 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	0.0039	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T;T;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.65	D;D;D;D;D
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.38	T
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		0.90, 0.48	.;P;P;.;.
Vest4		0.48
MutPred		0.85		.;Gain of MoRF binding (P = 0.0188);.;Gain of MoRF binding (P = 0.0188);Gain of MoRF binding (P = 0.0188);
MVP		0.24
MPC		0.58
ClinPred		0.83	D
GERP RS		5.9
Varity_R		0.58
gMVP		0.80

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: rs200317239; hg19: chr6-75844564;