chr7-157367435-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_058246.4(DNAJB6):​c.298T>G​(p.Phe100Val) 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F100S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

DNAJB6
NM_058246.4 missense

Scores

11
6
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.13
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_058246.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.867
PP5
Variant 7-157367435-T-G is Pathogenic according to our data. Variant chr7-157367435-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 225174.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DNAJB6NM_058246.4 linkuse as main transcriptc.298T>G p.Phe100Val missense_variant 5/10 ENST00000262177.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DNAJB6ENST00000262177.9 linkuse as main transcriptc.298T>G p.Phe100Val missense_variant 5/101 NM_058246.4 O75190-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 26, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Benign
0.21
T;.;D;.;T;.;T
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
D;D;D;D;D;D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.87
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.72
D
MutationAssessor
Pathogenic
3.8
.;H;H;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-6.9
D;D;D;D;D;D;.
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D;D;D;D;D;D;.
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D
Polyphen
1.0, 1.0
.;D;D;.;D;.;.
Vest4
0.90, 0.95, 0.85, 0.96
MutPred
0.50
Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);
MVP
0.92
MPC
1.3
ClinPred
1.0
D
GERP RS
4.6
Varity_R
0.84
gMVP
0.97

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs869320700; hg19: chr7-157160129; API