Genetic Variant NM_080680.3:c.1181G>T (chr6-33181004-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_080680.3(COL11A2):c.1181G>T(p.Gly394Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

COL11A2
NM_080680.3 missense, splice_region

Scores

Splicing: ADA: 0.7499

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.65

Variant links:

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]

COL11A2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL11A2	NM_080680.3 link	c.1181G>T	p.Gly394Val	missense_variant, splice_region_variant	Exon 10 of 66	ENST00000341947.7	NP_542411.2	P13942A0A0C4DFS1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7 link	c.1181G>T	p.Gly394Val	missense_variant, splice_region_variant	Exon 10 of 66	5	NM_080680.3	ENSP00000339915.2		A0A0C4DFS1
COL11A2	ENST00000374708.8 link	c.923G>T	p.Gly308Val	missense_variant, splice_region_variant	Exon 8 of 64	5		ENSP00000363840.4		Q4VXY6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.082

T;T;.;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Pathogenic

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-7.5

D;D;D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.021

D;D;D;D

Sift4G

Benign

0.13

T;T;T;D

Vest4

0.86

MutPred

0.34

.;Gain of solvent accessibility (P = 0.2689);.;Gain of solvent accessibility (P = 0.2689);

MVP

0.93

MPC

1.2

ClinPred

1.0

GERP RS

3.7

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.75

dbscSNV1_RF

Benign

0.61

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over