chr7-157367408-T-C

Variant names:

• chr7-157367408-T-C
• rs869320701
• NM_058246.4:c.271T>C

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP5_Very_Strong

The ENST00000262177.9(DNAJB6):​c.271T>C​(p.Phe91Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F91V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAJB6 ENST00000262177.9 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.13
• Publications: 0 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 22 ACMG points.

• PS1: Transcript ENST00000262177.9 (DNAJB6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000262177.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-157367408-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 498056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 7-157367408-T-C is Pathogenic according to our data. Variant chr7-157367408-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1322758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000262177.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB6	NM_058246.4	MANE Select	c.271T>C	p.Phe91Leu	missense	Exon 5 of 10	NP_490647.1
	DNAJB6	NM_005494.3		c.271T>C	p.Phe91Leu	missense	Exon 5 of 8	NP_005485.1
	DNAJB6	NM_001363676.1		c.271T>C	p.Phe91Leu	missense	Exon 5 of 7	NP_001350605.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB6	ENST00000262177.9	TSL:1 MANE Select	c.271T>C	p.Phe91Leu	missense	Exon 5 of 10	ENSP00000262177.4
	DNAJB6	ENST00000429029.6	TSL:1	c.271T>C	p.Phe91Leu	missense	Exon 5 of 8	ENSP00000397556.2
	DNAJB6	ENST00000459889.5	TSL:1	n.271T>C		non_coding_transcript_exon	Exon 5 of 10	ENSP00000488263.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.1
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.27		Gain of catalytic residue at F91 (P = 0.1463)
MVP		0.88
MPC		1.0
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.69
gMVP		0.95
Mutation Taster		=2/98	disease causing

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: rs869320701; hg19: chr7-157160102;