rs387907046

Variant names:

• chr7-157367414-T-C
• rs387907046
• NM_058246.4:c.277T>C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS1_Very_Strong PM1 PM2 PP3 PP5_Moderate

The NM_058246.4(DNAJB6):​c.277T>C​(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 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)
• Consequence: DNAJB6 NM_058246.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.13
• Publications: 7 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 15 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 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751
• PP5: Variant 7-157367414-T-C is Pathogenic according to our data. Variant chr7-157367414-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 30904.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJB6	NM_058246.4	c.277T>C	p.Phe93Leu	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.277T>C	p.Phe93Leu	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

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Aug 08, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;D;.;T;.;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	T;T;T;T;T;T;T;T
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.2	.;M;M;.;.;.;.;.
PhyloP100		7.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.9	D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.66
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		0.90
MPC		1.1
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.62
gMVP		0.96
Mutation Taster		=1/99	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: rs387907046; hg19: chr7-157160108;