NM_058246.4:c.265T>C

Variant names:

• chr7-157367402-T-C
• rs387907150
• NM_058246.4:c.265T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP5 BP4

The NM_058246.4(DNAJB6):​c.265T>C​(p.Phe89Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F89I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAJB6 NM_058246.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 2.73
• Publications: 25 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr7-157367402-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 31531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 7-157367402-T-C is Pathogenic according to our data. Variant chr7-157367402-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 427160.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19515404). . Strength limited to SUPPORTING due to the PP5.

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.265T>C	p.Phe89Leu	missense	Exon 5 of 10	NP_490647.1	O75190-1
	DNAJB6	NM_005494.3		c.265T>C	p.Phe89Leu	missense	Exon 5 of 8	NP_005485.1	O75190-2
	DNAJB6	NM_001363676.1		c.265T>C	p.Phe89Leu	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.265T>C	p.Phe89Leu	missense	Exon 5 of 10	ENSP00000262177.4	O75190-1
	DNAJB6	ENST00000429029.6	TSL:1	c.265T>C	p.Phe89Leu	missense	Exon 5 of 8	ENSP00000397556.2	O75190-2
	DNAJB6	ENST00000459889.5	TSL:1	n.265T>C		non_coding_transcript_exon	Exon 5 of 10	ENSP00000488263.1	A0A0J9YX62

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.092	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		2.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.28
Sift	Benign	0.034	D
Sift4G	Benign	0.074	T
Polyphen		0.0040	B
Vest4		0.58
MutPred		0.27		Gain of relative solvent accessibility (P = 0.1571)
MVP		0.78
MPC		0.90
ClinPred		0.96	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.42
gMVP		0.89
Mutation Taster		=29/71	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: rs387907150; hg19: chr7-157160096;