6-75132006-A-T

Position:

• chr6-75132006-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004370.6(COL12A1):​c.5871T>A​(p.Ala1957Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.881 in 1,613,972 control chromosomes in the GnomAD database, including 627,348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (58810 hom., cov: 32)
  • Exomes 𝑓: 0.88 (568538 hom.)
• Consequence: COL12A1 NM_004370.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.66

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 6-75132006-A-T is Benign according to our data. Variant chr6-75132006-A-T is described in ClinVar as [Benign]. Clinvar id is 259341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75132006-A-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.66 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.5871T>A	p.Ala1957Ala	synonymous_variant	35/66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.5871T>A	p.Ala1957Ala	synonymous_variant	35/66	1	NM_004370.6	ENSP00000325146.8
COL12A1	ENST00000345356.10	c.2379T>A	p.Ala793Ala	synonymous_variant	20/51	1		ENSP00000305147.9
COL12A1	ENST00000483888.6	c.5871T>A	p.Ala1957Ala	synonymous_variant	35/65	5		ENSP00000421216.1
COL12A1	ENST00000416123.6	c.5871T>A	p.Ala1957Ala	synonymous_variant	34/63	5		ENSP00000412864.2

Frequencies

GnomAD3 genomes AF: 0.879 AC: 133622 AN: 152072 Hom.: 58758 Cov.: 32

Gnomad AFR AF: 0.869

Gnomad AMI AF: 0.741

Gnomad AMR AF: 0.900

Gnomad ASJ AF: 0.896

Gnomad EAS AF: 0.860

Gnomad SAS AF: 0.865

Gnomad FIN AF: 0.886

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.882

Gnomad OTH AF: 0.875

GnomAD3 exomes AF: 0.887 AC: 221131 AN: 249340 Hom.: 98156 AF XY: 0.883 AC XY: 119394 AN XY: 135260

Gnomad AFR exome AF: 0.870

Gnomad AMR exome AF: 0.931

Gnomad ASJ exome AF: 0.896

Gnomad EAS exome AF: 0.872

Gnomad SAS exome AF: 0.863

Gnomad FIN exome AF: 0.890

Gnomad NFE exome AF: 0.883

Gnomad OTH exome AF: 0.885

GnomAD4 exome AF: 0.882 AC: 1288908 AN: 1461782 Hom.: 568538 Cov.: 53 AF XY: 0.881 AC XY: 640323 AN XY: 727192

Gnomad4 AFR exome AF: 0.877

Gnomad4 AMR exome AF: 0.927

Gnomad4 ASJ exome AF: 0.898

Gnomad4 EAS exome AF: 0.856

Gnomad4 SAS exome AF: 0.862

Gnomad4 FIN exome AF: 0.892

Gnomad4 NFE exome AF: 0.882

Gnomad4 OTH exome AF: 0.878

GnomAD4 genome AF: 0.879 AC: 133732 AN: 152190 Hom.: 58810 Cov.: 32 AF XY: 0.880 AC XY: 65438 AN XY: 74396

Gnomad4 AFR AF: 0.869

Gnomad4 AMR AF: 0.900

Gnomad4 ASJ AF: 0.896

Gnomad4 EAS AF: 0.861

Gnomad4 SAS AF: 0.864

Gnomad4 FIN AF: 0.886

Gnomad4 NFE AF: 0.882

Gnomad4 OTH AF: 0.876

Alfa AF: 0.882 Hom.: 14747

Bravo AF: 0.881

Asia WGS AF: 0.859 AC: 2989 AN: 3478

EpiCase AF: 0.883

EpiControl AF: 0.881

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Bethlem myopathy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2018

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Ullrich congenital muscular dystrophy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.095
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs594012; hg19: chr6-75841722;