rs115246424

chr6-75145403-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BS1_Supporting

The NM_004370.6(COL12A1):c.4613A>G(p.Asn1538Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000706 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1538D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 4.76

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 Likely_benign. Variant got -2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL12A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.100661814).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000243 (37/152288) while in subpopulation AFR AF= 0.000721 (30/41582). AF 95% confidence interval is 0.000518. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.4613A>G	p.Asn1538Ser	missense_variant	25/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.4613A>G	p.Asn1538Ser	missense_variant	25/66	1	NM_004370.6	P4

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000144 AC: 36 AN: 249232 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135200

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000613

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000527 AC: 77 AN: 1461734 Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 32 AN XY: 727166

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74466

Gnomad4 AFR AF: 0.000721

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000322 Hom.: 0

Bravo AF: 0.000321

ESP6500AA AF: 0.000718 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000991 AC: 12

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 28, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 23, 2021

Variant summary: COL12A1 c.4613A>G (p.Asn1538Ser) results in a conservative amino acid change located in the Fibronectin type III 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 0.00014 in 249232 control chromosomes. To our knowledge, no occurrence of c.4613A>G in individuals affected with Bethlem Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2023

The c.4613A>G (p.N1538S) alteration is located in exon 25 (coding exon 24) of the COL12A1 gene. This alteration results from a A to G substitution at nucleotide position 4613, causing the asparagine (N) at amino acid position 1538 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.028	T;T;.;.;.
Eigen	Benign	-0.086
Eigen_PC	Benign	-0.051
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.94	D;D;D;D
PrimateAI	Benign	0.39	T
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		0.75, 0.36	.;P;B;.;.
Vest4		0.31
MVP		0.58
MPC		0.099
ClinPred		0.026	T
GERP RS		4.1
Varity_R		0.040
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs115246424; hg19: chr6-75855119;