7-157367416-C-G

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1_Very_Strong PM1 PM2 PP3 PP5_Very_Strong

The NM_058246.4(DNAJB6):c.279C>G(p.Phe93Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. F93F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAJB6 NM_058246.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.03

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]

ACMG classification

Verdict is Pathogenic. Variant got 21 ACMG points.

• PS1: Transcript NM_058246.4 (DNAJB6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 31530
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_058246.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745
• PP5: Variant 7-157367416-C-G is Pathogenic according to our data. Variant chr7-157367416-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 31529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-157367416-C-G is described in Lovd as [Pathogenic]. Variant chr7-157367416-C-G is described in Lovd as [Pathogenic]. Variant chr7-157367416-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJB6	NM_058246.4	c.279C>G	p.Phe93Leu	missense_variant	5/10	ENST00000262177.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJB6	ENST00000262177.9	c.279C>G	p.Phe93Leu	missense_variant	5/10	1	NM_058246.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 10, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 26, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 27, 2023	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 93 of the DNAJB6 protein (p.Phe93Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant limb-girdle muscular dystrophy (PMID: 22334415, 26205529, 26847086, 28794355). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31529). 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) performed at Invitae indicates that this missense variant is expected to disrupt DNAJB6 protein function. Experimental studies have shown that this missense change affects DNAJB6 function (PMID: 26847086). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Oct 11, 2022	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 09, 2021	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. In vitro and in vivo experiments showed that this variant has a dominant toxic effect on the wild-type protein (PMID: 22366786). -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	DNAJB6: PS1, PM2, PM5, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2017	The pathogenic F93L variant in the DNAJB6 gene has been reported multiple times in association with LGMD1D (Sarparanta et al., 2012; Sato et al., 2013; Sandell et al., 2016). Functional studies indicate that F93L increases the half-life of DNAJB6, which results in the toxic aggregation of DNAJB6 protein and its binding partners (Sarparanta et al., 2012). The F93L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although F93L is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved across species. Additionally, missense variants in the same residue (F93I) and in nearby residues (F89I; F91I; P96R) have been reported in the Human Gene Mutation Database in association with myopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret F93L as a pathogenic variant, and its presence is consistent with a diagnosis of LGMD1D. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;D;.;T;.;T;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T;T;T;T;T;T;T;T
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.74	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.9	D;D;D;D;D;D;D;.
REVEL	Uncertain	0.60
Sift	Benign	0.039	D;D;D;D;D;T;T;.
Sift4G	Uncertain	0.059	T;T;T;D;T;T;T;T
Polyphen		1.0, 0.97, 0.20	.;D;D;.;B;.;.;.
Vest4		0.93, 0.94, 0.80, 0.96
MutPred		0.29		Loss of phosphorylation at T92 (P = 0.2306);Loss of phosphorylation at T92 (P = 0.2306);Loss of phosphorylation at T92 (P = 0.2306);Loss of phosphorylation at T92 (P = 0.2306);Loss of phosphorylation at T92 (P = 0.2306);Loss of phosphorylation at T92 (P = 0.2306);Loss of phosphorylation at T92 (P = 0.2306);Loss of phosphorylation at T92 (P = 0.2306);
MVP		0.87
MPC		1.1
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.60
gMVP		0.96

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

Other links and lift over

dbSNP: rs149278319; hg19: chr7-157160110;