rs759982570

Variant names:

• chr7-157367410-C-G
• rs759982570
• NM_058246.4:c.273C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-157367410-C-G
• chr7-157367410-C-T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP5_Very_Strong

The NM_058246.4(DNAJB6):​c.273C>G​(p.Phe91Leu) 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 Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F91V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAJB6 NM_058246.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.53
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6)

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS1: Transcript NM_058246.4 (DNAJB6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_058246.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-157367408-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 498056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 7-157367410-C-G is Pathogenic according to our data. Variant chr7-157367410-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 225176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJB6	NM_058246.4	c.273C>G	p.Phe91Leu	missense_variant	Exon 5 of 10	ENST00000262177.9	NP_490647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJB6	ENST00000262177.9	c.273C>G	p.Phe91Leu	missense_variant	Exon 5 of 10	1	NM_058246.4	ENSP00000262177.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) Pathogenic:3

Sep 27, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 01, 2020

Neuromuscular Department, Shariati Hospital, Tehran University of Medical Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

34-year-old male, with proximal weakness since age of 15 years. He had also distal weakness mostly in hands. Muscle biopsy revealed rimmed vacuoles, and core bodies. -

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 91 of the DNAJB6 protein (p.Phe91Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 26205529, 26338452, 26371419). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225176). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DNAJB6 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DNAJB6 function (PMID: 26338452, 26371419). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Dec 08, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Abnormality of the musculature Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;D;.;T;.;T;T
Eigen	Benign	-0.0053
Eigen_PC	Benign	-0.065
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.71	T;T;T;T;T;T;T;T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.095	T
MutationAssessor	Uncertain	2.8	.;M;M;.;.;.;.;.
PhyloP100		1.5
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.5	D;D;D;D;D;D;D;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.015	D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.024	D;T;D;D;D;D;D;D
Polyphen		1.0, 0.94, 0.43	.;D;P;.;B;.;.;.
Vest4		0.91, 0.93, 0.78, 0.97
MutPred		0.27		Gain of catalytic residue at F91 (P = 0.1463);Gain of catalytic residue at F91 (P = 0.1463);Gain of catalytic residue at F91 (P = 0.1463);Gain of catalytic residue at F91 (P = 0.1463);Gain of catalytic residue at F91 (P = 0.1463);Gain of catalytic residue at F91 (P = 0.1463);Gain of catalytic residue at F91 (P = 0.1463);Gain of catalytic residue at F91 (P = 0.1463);
MVP		0.95
MPC		1.0
ClinPred		0.97	D
GERP RS		0.53
Varity_R		0.43
gMVP		0.95
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs759982570; hg19: chr7-157160104;