19-41354765-C-T

Position:

chr19-41354765-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_030578.4(B9D2):c.463G>A(p.Gly155Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

B9D2
NM_030578.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.38

Variant links:

Genes affected

B9D2 (HGNC:28636): (B9 domain containing 2) This gene encodes a B9 domain protein, which are exclusively found in ciliated organisms. The gene is upregulated during mucociliary differentiation, and the encoded protein localizes to basal bodies and cilia. Disrupting expression of this gene results in ciliogenesis defects. [provided by RefSeq, Oct 2009]

B9D2 links:

TMEM91 (HGNC:32393): (transmembrane protein 91) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle and membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM91 links:

ENSG00000255730 (HGNC:):

ENSG00000255730 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 19-41354765-C-T is Pathogenic according to our data. Variant chr19-41354765-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
B9D2	NM_030578.4 linkuse as main transcript	c.463G>A	p.Gly155Ser	missense_variant	4/4	ENST00000243578.8	NP_085055.2	Q9BPU9
B9D2	XM_011527349.3 linkuse as main transcript	c.463G>A	p.Gly155Ser	missense_variant	4/4		XP_011525651.1	Q9BPU9
B9D2	XM_011527350.3 linkuse as main transcript	c.304G>A	p.Gly102Ser	missense_variant	3/3		XP_011525652.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
B9D2	ENST00000243578.8 linkuse as main transcript	c.463G>A	p.Gly155Ser	missense_variant	4/4	1	NM_030578.4	ENSP00000243578.2		Q9BPU9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250880

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461714

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727178

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Joubert syndrome 34

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2015

- -

Joubert syndrome and related disorders

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Feb 18, 2022

Variant summary: B9D2 c.463G>A (p.Gly155Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250880 control chromosomes (gnomAD). The variant, c.463G>A, has been reported in the literature in a compound heterozygous individual affected with Joubert Syndrome, who carried the variant c.220C>T (p.Pro74Ser) in trans (Bachmann-Gagescu_2015). A recent publication reported experimental evidence characterizing both variants alone and together in a C. elegans model system, and demonstrated that the cellular level, localization and function were moderately (P74S) or severely (G155S) altered, confirming that both variant alleles are pathogenic in worms, and compound heterozygous worms phenocopy worms homozygous for P74S (Lange_2021). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Familial aplasia of the vermis

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

UW Hindbrain Malformation Research Program, University of Washington

Feb 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Benign

0.10

Eigen_PC

Benign

0.039

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.7

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.82

Sift

Uncertain

0.017

Sift4G

Pathogenic

0.0

Polyphen

0.26

Vest4

0.91

MutPred

0.92

Gain of glycosylation at G155 (P = 0.0385);

MVP

0.84

MPC

0.69

ClinPred

0.99

GERP RS

3.0

Varity_R

0.77

gMVP

0.82

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over