rs1554217436

Variant names:

• chr6-33172294-T-C
• rs1554217436
• NM_080680.3:c.2983A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-33172294-T-C
• chr6-33172294-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_080680.3(COL11A2):​c.2983A>G​(p.Thr995Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000837 in 1,433,232 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.493

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15987498).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.2983A>G	p.Thr995Ala	missense_variant	Exon 40 of 66	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.2983A>G	p.Thr995Ala	missense_variant	Exon 40 of 66	5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000374708.8	c.2725A>G	p.Thr909Ala	missense_variant	Exon 38 of 64	5		ENSP00000363840.4
COL11A2	ENST00000477772.1	n.272+4715A>G		intron_variant	Intron 5 of 8	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000837 AC: 12 AN: 1433232 Hom.: 0 Cov.: 33 AF XY: 0.00000422 AC XY: 3 AN XY: 710306

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000100

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr995Ala variant in COL11A2 has not been previously reported in individua ls with hearing loss or in large population studies. Computational prediction t ools and conservation analyses do not provide strong support for or against an i mpact to the protein. In summary, the clinical significance of the p.Thr995Ala v ariant is uncertain. ACMG/AMP criteria applied: PM2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.0038	T;T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.57	T
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.61	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Vest4		0.26
MVP		0.60
MPC		0.58
ClinPred		0.36	T
GERP RS		4.4
gMVP		0.23

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: rs1554217436; hg19: chr6-33140071;