rs201988277

chr6-75113301-G-Achr6-75113301-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BS1_Supporting

The NM_004370.6(COL12A1):c.7853C>T(p.Thr2618Met) variant causes a missense change. The variant allele was found at a frequency of 0.000394 in 1,547,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T2618T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1 O:1
• Conservation: PhyloP100: 6.22

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 Likely_benign. Variant got -2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL12A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0746977).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000405 (565/1395994) while in subpopulation NFE AF= 0.000456 (494/1083068). AF 95% confidence interval is 0.000423. There are 0 homozygotes in gnomad4_exome. There are 273 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.7853C>T	p.Thr2618Met	missense_variant	51/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.7853C>T	p.Thr2618Met	missense_variant	51/66	1	NM_004370.6	P4

Frequencies

GnomAD3 genomes AF: 0.000297 AC: 45 AN: 151686 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000854

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000458

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000300 AC: 62 AN: 206788 Hom.: 0 AF XY: 0.000325 AC XY: 37 AN XY: 113724

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: 0.0000417

Gnomad FIN exome AF: 0.000939

Gnomad NFE exome AF: 0.000417

Gnomad OTH exome AF: 0.000418

GnomAD4 exome AF: 0.000405 AC: 565 AN: 1395994 Hom.: 0 Cov.: 28 AF XY: 0.000394 AC XY: 273 AN XY: 693284

Gnomad4 AFR exome AF: 0.000167

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000276

Gnomad4 SAS exome AF: 0.0000135

Gnomad4 FIN exome AF: 0.000855

Gnomad4 NFE exome AF: 0.000456

Gnomad4 OTH exome AF: 0.000313

GnomAD4 genome AF: 0.000296 AC: 45 AN: 151802 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74214

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000854

Gnomad4 NFE AF: 0.000458

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000425 Hom.: 0

Bravo AF: 0.000204

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000493 AC: 4

ExAC AF: 0.000273 AC: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 22, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 06, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2023	Has been reported as likely pathogenic in a female with clinical features of Ehlers-Danlos syndrome (Fajardo-Jimenez et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32214361, 36421793) -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 04-23-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.33
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.075	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.63	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.3	D;.;D;D;D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D;.;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		1.0	.;.;D;D;.;.;.
Vest4		0.40, 0.51, 0.61, 0.64, 0.54
MVP		0.56
MPC		0.99
ClinPred		0.34	T
GERP RS		5.8
Varity_R		0.23
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs201988277; hg19: chr6-75823017; COSMIC: COSV59393046;