NM_080680.3:c.4943A>T

Variant names:

• chr6-33164394-T-A
• rs1487325262
• NM_080680.3:c.4943A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_080680.3(COL11A2):​c.4943A>T​(p.His1648Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.19

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-33164394-T-A is Pathogenic according to our data. Variant chr6-33164394-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 506216.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.4943A>T	p.His1648Leu	missense_variant	Exon 65 of 66	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.4943A>T	p.His1648Leu	missense_variant	Exon 65 of 66	5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000374708.8	c.4685A>T	p.His1562Leu	missense_variant	Exon 63 of 64	5		ENSP00000363840.4
COL11A2	ENST00000477772.1	n.733A>T		non_coding_transcript_exon_variant	Exon 8 of 9	2
COL11A2	ENST00000683572.1	n.749A>T		non_coding_transcript_exon_variant	Exon 8 of 9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Jun 08, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.His1648Leu variant in COL11A2 variant has been reported by our laboratory in 2 individuals with hearing loss, including one individual in whom a likely pathogenic COL11A2 variant was confirmed in trans and both variants segregated in an affected sibling. None of the affected individuals harboring this variant were reported to have clinical features of Stickler or OSMED syndrome. The p.His1648Leu variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PM2, PM3, PP3, PP1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.073	T;T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.043
FATHMM_MKL	Benign	0.74	D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Benign	-0.60	T
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Uncertain	0.42
Sift	Benign	0.038	D;D;D
Sift4G	Benign	0.15	T;T;T
Vest4		0.60
MutPred		0.65		.;Loss of solvent accessibility (P = 0.086);.;
MVP		0.62
MPC		0.42
ClinPred		0.95	D
GERP RS		3.7
gMVP		0.73

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: rs1487325262; hg19: chr6-33132171;