6-75132038-G-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.5839C>A(p.Pro1947Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,614,188 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. P1947L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 2.62

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=0.039941818).
• BP6: Variant 6-75132038-G-T is Benign according to our data. Variant chr6-75132038-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475878.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000189 (276/1461832) while in subpopulation MID AF= 0.00295 (17/5768). AF 95% confidence interval is 0.00188. There are 1 homozygotes in gnomad4_exome. There are 146 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.5839C>A	p.Pro1947Thr	missense_variant	35/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.5839C>A	p.Pro1947Thr	missense_variant	35/66	1	NM_004370.6	P4
COL12A1	ENST00000345356.10	c.2347C>A	p.Pro783Thr	missense_variant	20/51	1
COL12A1	ENST00000483888.6	c.5839C>A	p.Pro1947Thr	missense_variant	35/65	5		A1
COL12A1	ENST00000416123.6	c.5839C>A	p.Pro1947Thr	missense_variant	34/63	5

Frequencies

GnomAD3 genomes AF: 0.000236 AC: 36 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000169 AC: 42 AN: 249256 Hom.: 0 AF XY: 0.000178 AC XY: 24 AN XY: 135210

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000204

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000189 AC: 276 AN: 1461832 Hom.: 1 Cov.: 33 AF XY: 0.000201 AC XY: 146 AN XY: 727216

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000186

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74500

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000137 Hom.: 0

Bravo AF: 0.000348

ESP6500AA AF: 0.000496 AC: 2

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000190 AC: 23

EpiCase AF: 0.000491

EpiControl AF: 0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 16, 2023	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 03, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2021	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 475878; Landrum et al., 2016) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	17
Dann	Benign	0.093
DEOGEN2	Benign	0.012	T;T;.;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	0.025
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.040	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Uncertain	0.56	T
Sift4G	Benign	0.58	T;T;T;T;T
Polyphen		0.021, 0.0040	.;B;B;.;.
Vest4		0.12
MVP		0.23
MPC		0.21
ClinPred		0.030	T
GERP RS		6.2
Varity_R		0.088
gMVP		0.52

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: rs191233787; hg19: chr6-75841754;