rs543145528

chr6-33167839-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_080680.3(COL11A2):c.3974C>T(p.Ser1325Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000315 in 1,612,898 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1325S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (7 hom.)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.79

Genes affected

COL11A2 (HGNC:2187): (collagen type XI alpha 2 chain) This gene encodes one of the two alpha chains of type XI collagen, a minor fibrillar collagen. It is located on chromosome 6 very close to but separate from the gene for retinoid X receptor beta. Type XI collagen is a heterotrimer but the third alpha chain is a post-translationally modified alpha 1 type II chain. Proteolytic processing of this type XI chain produces PARP, a proline/arginine-rich protein that is an amino terminal domain. Mutations in this gene are associated with type III Stickler syndrome, otospondylomegaepiphyseal dysplasia (OSMED syndrome), Weissenbacher-Zweymuller syndrome, autosomal dominant non-syndromic sensorineural type 13 deafness (DFNA13), and autosomal recessive non-syndromic sensorineural type 53 deafness (DFNB53). Alternative splicing results in multiple transcript variants. A related pseudogene is located nearby on chromosome 6. [provided by RefSeq, Jul 2009]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL11A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.008990198).
• BP6: Variant 6-33167839-G-A is Benign according to our data. Variant chr6-33167839-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 561275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33167839-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000256 (39/152214) while in subpopulation SAS AF= 0.00684 (33/4826). AF 95% confidence interval is 0.005. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL11A2	NM_080680.3	c.3974C>T	p.Ser1325Leu	missense_variant	55/66	ENST00000341947.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL11A2	ENST00000341947.7	c.3974C>T	p.Ser1325Leu	missense_variant	55/66	5	NM_080680.3	P4
COL11A2	ENST00000374708.8	c.3716C>T	p.Ser1239Leu	missense_variant	53/64	5		A1
COL11A2	ENST00000477772.1	n.273-2023C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000666 AC: 164 AN: 246208 Hom.: 2 AF XY: 0.000827 AC XY: 111 AN XY: 134244

Gnomad AFR exome AF: 0.0000662

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00211

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00432

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000272

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.000321 AC: 469 AN: 1460684 Hom.: 7 Cov.: 33 AF XY: 0.000433 AC XY: 315 AN XY: 726666

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00439

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74416

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000262 Hom.: 0

Bravo AF: 0.0000907

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000735 AC: 87

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 05, 2017	The p.Ser1325Leu variant (rs543145528) has not been reported in the medical literature, nor is it found in ClinVar. The p.Ser1325Leu variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.44% in the South Asian population (identified in 134 out of 30,530 chromosomes; 2 homozygotes). Additionally, the serine at codon 1325 is weakly conserved considering 11 species (Alamut software v2.9.0), and computational analyses suggest that this variant does not affect the COL11A2 protein structure/function (SIFT: tolerated, PolyPhen2: benign, MutationTaster: polymorphism). Therefore, based on the available evidence, the p.Ser1325Leu variant appears to be an ethnic-specific polymorphism present in the South Asian population and is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2021	- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.025	T;T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.0090	T;T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	0.95	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.30	T;T;T
Sift4G	Benign	0.10	T;T;T
Vest4		0.39
MVP		0.57
MPC		0.30
ClinPred		0.069	T
GERP RS		3.5
gMVP		0.27

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: rs543145528; hg19: chr6-33135616;