rs149278319

Positions:

• chr7-157367416-C-A
• chr7-157367416-C-G
• chr7-157367416-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1 PM1 PM2 PP5_Very_Strong

The NM_058246.4(DNAJB6):​c.279C>A​(p.Phe93Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,356 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Synonymous variant affecting the same amino acid position (i.e. F93F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNAJB6 NM_058246.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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]

DNAJB6 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PS1: Transcript NM_058246.4 (DNAJB6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a region_of_interest Interaction with HSP70 (size 144) in uniprot entity DNJB6_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_058246.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-157367416-C-A is Pathogenic according to our data. Variant chr7-157367416-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 31530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-157367416-C-A is described in Lovd as [Pathogenic]. Variant chr7-157367416-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJB6	NM_058246.4	c.279C>A	p.Phe93Leu	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	c.279C>A	p.Phe93Leu	missense_variant	5/10	1	NM_058246.4	ENSP00000262177.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251472 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135906

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461356 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727010

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 26, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2022	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 31530). This missense change has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (PMID: 22334415, 26205529, 26847086, 28794355, 30564623). This variant is not present in population databases (gnomAD no frequency). 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). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2018	The F93L pathogenic variant in the DNAJB6 gene has been previously reported in association with LGMD1D (Sarparanta et al., 2012). 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). Additional functional studies in animal models showed F93L resulted in muscle weakness compared to controls (Nam et al., 2015; Bengoechea et al., 2015). F93L is not observed in large population cohorts (Lek et al., 2016). The F93L variant is a conservative amino acid substitution; however, this substitution occurs at a position that is conserved, and a different nucleotide substitution (c.279 C>G) resulting in the same missense change, as well as missense variants in nearby residues (F89I; F91I/L; P96R) have been reported in the Human Gene Mutation Database in association with myopathy (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, F93L is interpreted to be a pathogenic variant. -

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	0.057	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	3.2	.;M;M;.;.;.;.;.
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;