rs387907150

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1PM2PM5PP5_Very_StrongBP4

The ENST00000262177.9(DNAJB6):c.265T>A(p.Phe89Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F89L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

DNAJB6
ENST00000262177.9 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.73

Variant links:

Genes affected

DNAJB6 (HGNC:14888): (DnaJ heat shock protein family (Hsp40) member B6) This gene encodes a member of the DNAJ protein family. DNAJ family members are characterized by a highly conserved amino acid stretch called the 'J-domain' and function as one of the two major classes of molecular chaperones involved in a wide range of cellular events, such as protein folding and oligomeric protein complex assembly. This family member may also play a role in polyglutamine aggregation in specific neurons. Alternative splicing of this gene results in multiple transcript variants; however, not all variants have been fully described. [provided by RefSeq, Jul 2008]

DNAJB6 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000262177.9

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-157367402-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 427160.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

PP5

Variant 7-157367402-T-A is Pathogenic according to our data. Variant chr7-157367402-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 31531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-157367402-T-A is described in Lovd as [Pathogenic]. Variant chr7-157367402-T-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.32345438). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJB6	NM_058246.4 linkuse as main transcript	c.265T>A	p.Phe89Ile	missense_variant	5/10	ENST00000262177.9	NP_490647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJB6	ENST00000262177.9 linkuse as main transcript	c.265T>A	p.Phe89Ile	missense_variant	5/10	1	NM_058246.4	ENSP00000262177		O75190-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6)

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2014	- -
Pathogenic, criteria provided, single submitter	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2023	This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 89 of the DNAJB6 protein (p.Phe89Ile). This variant is present in population databases (rs387907150, gnomAD 0.007%). This missense change has been observed in individual(s) with limb girdle muscular dystrophy type 1D (PMID: 22366786, 24594375). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31531). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNAJB6 protein function. Experimental studies have shown that this missense change affects DNAJB6 function (PMID: 22366786, 24920671, 26371419). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.088

T;.;D;.;T;.;T;T

Eigen

Benign

0.12

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.74

T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.32

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.28

MutationAssessor

Pathogenic

3.1

.;M;M;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-4.2

D;D;D;D;D;D;D;.

REVEL

Uncertain

0.47

Sift

Uncertain

0.010

D;D;D;D;D;D;T;.

Sift4G

Uncertain

0.056

T;T;T;T;D;T;T;T

Polyphen

0.018, 0.61, 0.16

.;B;P;.;B;.;.;.

Vest4

0.75, 0.78, 0.65, 0.84

MutPred

0.30

Loss of disorder (P = 0.1335);Loss of disorder (P = 0.1335);Loss of disorder (P = 0.1335);Loss of disorder (P = 0.1335);Loss of disorder (P = 0.1335);Loss of disorder (P = 0.1335);Loss of disorder (P = 0.1335);Loss of disorder (P = 0.1335);

MVP

0.95

MPC

0.85

ClinPred

0.96

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.38

gMVP

0.94

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