NM_058246.4:c.279C>A

Variant names:

• chr7-157367416-C-A
• rs149278319
• NM_058246.4:c.279C>A

Variant summary

Our verdict is Pathogenic. The variant received 24 ACMG points: 24P and 0B. PS1_Very_Strong PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000491751: 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" and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. 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
• Publications: 41 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 24 ACMG points.

• PS1: Transcript NM_058246.4 (DNAJB6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000491751: 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).
• PM1: In a hotspot region, there are 9 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
• PP5: Variant 7-157367416-C-A is Pathogenic according to our data. Variant chr7-157367416-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 31530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058246.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB6	NM_058246.4	MANE Select	c.279C>A	p.Phe93Leu	missense	Exon 5 of 10	NP_490647.1	O75190-1
	DNAJB6	NM_005494.3		c.279C>A	p.Phe93Leu	missense	Exon 5 of 8	NP_005485.1	O75190-2
	DNAJB6	NM_001363676.1		c.279C>A	p.Phe93Leu	missense	Exon 5 of 7	NP_001350605.1	E9PH18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB6	ENST00000262177.9	TSL:1 MANE Select	c.279C>A	p.Phe93Leu	missense	Exon 5 of 10	ENSP00000262177.4	O75190-1
	DNAJB6	ENST00000429029.6	TSL:1	c.279C>A	p.Phe93Leu	missense	Exon 5 of 8	ENSP00000397556.2	O75190-2
	DNAJB6	ENST00000459889.5	TSL:1	n.279C>A		non_coding_transcript_exon	Exon 5 of 10	ENSP00000488263.1	A0A0J9YX62

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251472 AF XY: 0.00000736

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111538

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) (2)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.60
Sift	Benign	0.039	D
Sift4G	Uncertain	0.059	T
Polyphen		1.0	D
Vest4		0.93
MutPred		0.29		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
Mutation Taster		=0/100	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: rs149278319; hg19: chr7-157160110;