NM_004370.6:c.4000+5G>A

Variant names:

• chr6-75151862-C-T
• rs181257320
• NM_004370.6:c.4000+5G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PP3_Strong BP6_Very_Strong BS1 BS2

The NM_004370.6(COL12A1):​c.4000+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00371 in 1,613,108 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (9 hom.)
• Consequence: COL12A1 NM_004370.6 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.54

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 -12 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 6-75151862-C-T is Benign according to our data. Variant chr6-75151862-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 475863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00333 (507/152146) while in subpopulation NFE AF= 0.00435 (296/68002). AF 95% confidence interval is 0.00394. There are 4 homozygotes in gnomad4. There are 261 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.4000+5G>A		splice_region_variant, intron_variant	Intron 20 of 65	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.4000+5G>A		splice_region_variant, intron_variant	Intron 20 of 65	1	NM_004370.6	ENSP00000325146.8

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 506 AN: 152028 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00277 AC: 688 AN: 248576 Hom.: 0 AF XY: 0.00279 AC XY: 376 AN XY: 134828

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.00559

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00128

Gnomad FIN exome AF: 0.00462

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00375 AC: 5473 AN: 1460962 Hom.: 9 Cov.: 31 AF XY: 0.00377 AC XY: 2741 AN XY: 726788

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00521

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00118

Gnomad4 FIN exome AF: 0.00540

Gnomad4 NFE exome AF: 0.00413

Gnomad4 OTH exome AF: 0.00364

GnomAD4 genome AF: 0.00333 AC: 507 AN: 152146 Hom.: 4 Cov.: 32 AF XY: 0.00351 AC XY: 261 AN XY: 74386

Gnomad4 AFR AF: 0.00263

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00443

Gnomad4 NFE AF: 0.00435

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00410 Hom.: 0

Bravo AF: 0.00299

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00306

EpiControl AF: 0.00326

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 09, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL12A1: BP4, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 31, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL12A1 c.4000+5G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0037 in 1460962 control chromosomes, including 9 homozygotes, predominantly at a frequency of 0.0054 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL12A1 causing Ullrich congenital muscular dystrophy 2 phenotype (0.0035). To our knowledge, no occurrence of c.4000+5G>A in individuals affected with Ullrich congenital muscular dystrophy 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 475863). Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.050		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: rs181257320; hg19: chr6-75861578;