rs35551395

chr6-75119098-C-Achr6-75119098-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004370.6(COL12A1):c.7299G>T(p.Thr2433=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,613,942 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2433T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (41 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (39 hom.)
• Consequence: COL12A1 NM_004370.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.41

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 6-75119098-C-A is Benign according to our data. Variant chr6-75119098-C-A is described in ClinVar as [Benign]. Clinvar id is 259345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75119098-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0128 (1945/152238) while in subpopulation AFR AF= 0.0421 (1751/41560). AF 95% confidence interval is 0.0405. There are 41 homozygotes in gnomad4. There are 916 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 41 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.7299G>T	p.Thr2433=	synonymous_variant	46/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.7299G>T	p.Thr2433=	synonymous_variant	46/66	1	NM_004370.6	P4

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1949 AN: 152120 Hom.: 41 Cov.: 33

Gnomad AFR AF: 0.0423

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00806

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00392 AC: 977 AN: 249376 Hom.: 22 AF XY: 0.00299 AC XY: 405 AN XY: 135282

Gnomad AFR exome AF: 0.0464

Gnomad AMR exome AF: 0.00426

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000663

Gnomad OTH exome AF: 0.00446

GnomAD4 exome AF: 0.00166 AC: 2431 AN: 1461704 Hom.: 39 Cov.: 31 AF XY: 0.00145 AC XY: 1051 AN XY: 727154

Gnomad4 AFR exome AF: 0.0421

Gnomad4 AMR exome AF: 0.00441

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000458

Gnomad4 OTH exome AF: 0.00427

GnomAD4 genome AF: 0.0128 AC: 1945 AN: 152238 Hom.: 41 Cov.: 33 AF XY: 0.0123 AC XY: 916 AN XY: 74426

Gnomad4 AFR AF: 0.0421

Gnomad4 AMR AF: 0.00805

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00389 Hom.: 5

Bravo AF: 0.0146

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000948

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

Oct 11, 2018

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.033
Dann	Benign	0.72

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: rs35551395; hg19: chr6-75828814;