rs35170847

chr6-75175267-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004370.6(COL12A1):c.2481G>A(p.Thr827=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000958 in 1,614,142 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (4 hom.)
• Consequence: COL12A1 NM_004370.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.229

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 6-75175267-C-T is Benign according to our data. Variant chr6-75175267-C-T is described in ClinVar as [Benign]. Clinvar id is 259326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75175267-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.229 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00474 (721/152260) while in subpopulation AFR AF= 0.0161 (670/41532). AF 95% confidence interval is 0.0151. There are 6 homozygotes in gnomad4. There are 328 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.2481G>A	p.Thr827=	synonymous_variant	13/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.2481G>A	p.Thr827=	synonymous_variant	13/66	1	NM_004370.6	P4
COL12A1	ENST00000345356.10	c.74-22785G>A		intron_variant		1
COL12A1	ENST00000483888.6	c.2481G>A	p.Thr827=	synonymous_variant	13/65	5		A1
COL12A1	ENST00000416123.6	c.2481G>A	p.Thr827=	synonymous_variant	12/63	5

Frequencies

GnomAD3 genomes AF: 0.00471 AC: 717 AN: 152142 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00134 AC: 333 AN: 249312 Hom.: 1 AF XY: 0.00112 AC XY: 151 AN XY: 135252

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000973

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000565 AC: 826 AN: 1461882 Hom.: 4 Cov.: 31 AF XY: 0.000536 AC XY: 390 AN XY: 727242

Gnomad4 AFR exome AF: 0.0184

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00474 AC: 721 AN: 152260 Hom.: 6 Cov.: 32 AF XY: 0.00441 AC XY: 328 AN XY: 74452

Gnomad4 AFR AF: 0.0161

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00223 Hom.: 0

Bravo AF: 0.00546

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
Cadd	Benign	7.7
Dann	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs35170847; hg19: chr6-75884983; COSMIC: COSV59392083; COSMIC: COSV59392083;