6-75132038-G-T

Variant names:

• chr6-75132038-G-T
• rs191233787
• NM_004370.6:c.5839C>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. 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).

• 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:3
• 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 -9 ACMG points.

• 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: {Likely_benign=3, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000236 (36/152356) while in subpopulation AFR AF= 0.000361 (15/41594). AF 95% confidence interval is 0.000222. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.5839C>A	p.Pro1947Thr	missense_variant	Exon 35 of 66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.5839C>A	p.Pro1947Thr	missense_variant	Exon 35 of 66	1	NM_004370.6	ENSP00000325146.8
COL12A1	ENST00000345356.10	c.2347C>A	p.Pro783Thr	missense_variant	Exon 20 of 51	1		ENSP00000305147.9
COL12A1	ENST00000483888.6	c.5839C>A	p.Pro1947Thr	missense_variant	Exon 35 of 65	5		ENSP00000421216.1
COL12A1	ENST00000416123.6	c.5839C>A	p.Pro1947Thr	missense_variant	Exon 34 of 63	5		ENSP00000412864.2

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:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Aug 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 16, 2023

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

Nov 01, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Mar 03, 2023

Revvity Omics, Revvity

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Dec 16, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL12A1 c.5839C>A (p.Pro1947Thr) results in a non-conservative amino acid change located in the Fibronectin type III repeat domain (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 1614188 control chromosomes in the gnomAD database (v4.1 dataset), including 1 homozygote. To our knowledge, no occurrence of c.5839C>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: 475878). Based on the evidence outlined above, the variant was classified as likely benign. -

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
MutationAssessor	Benign	0.070	.;N;.;N;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.87	.;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	1.0	.;T;T;T;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;