rs200315815

chr6-75181206-C-Achr6-75181206-C-Gchr6-75181206-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_004370.6(COL12A1):c.1897G>T(p.Val633Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,507,156 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V633I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.285

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 Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL12A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.008966267).
• BP6: Variant 6-75181206-C-A is Benign according to our data. Variant chr6-75181206-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475849.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00251 (215/85602) while in subpopulation AFR AF= 0.00871 (205/23532). AF 95% confidence interval is 0.00773. There are 0 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.1897G>T	p.Val633Phe	missense_variant	11/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.1897G>T	p.Val633Phe	missense_variant	11/66	1	NM_004370.6	P4

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 215 AN: 85518 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00874

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00143

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000963

GnomAD3 exomes AF: 0.000447 AC: 88 AN: 196792 Hom.: 0 AF XY: 0.000295 AC XY: 32 AN XY: 108634

Gnomad AFR exome AF: 0.00474

Gnomad AMR exome AF: 0.000841

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: 0.0000321

Gnomad OTH exome AF: 0.000453

GnomAD4 exome AF: 0.000146 AC: 207 AN: 1421554 Hom.: 0 Cov.: 31 AF XY: 0.000103 AC XY: 73 AN XY: 706022

Gnomad4 AFR exome AF: 0.00501

Gnomad4 AMR exome AF: 0.000694

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: 0.00000823

Gnomad4 OTH exome AF: 0.000239

GnomAD4 genome AF: 0.00251 AC: 215 AN: 85602 Hom.: 0 Cov.: 31 AF XY: 0.00246 AC XY: 100 AN XY: 40718

Gnomad4 AFR AF: 0.00871

Gnomad4 AMR AF: 0.00143

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.00178

ESP6500AA AF: 0.00354 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000506 AC: 61

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 12, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2020	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	-0.061
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.0090	T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.0	M;M;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.040	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.98	D;.;P
Vest4		0.19
MVP		0.58
MPC		0.22
ClinPred		0.011	T
GERP RS		4.8
Varity_R		0.088
gMVP		0.66

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: rs200315815; hg19: chr6-75890922;