rs147168661

Positions:

• chr7-157416078-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_058246.4(DNAJB6):​c.961T>C​(p.Ser321Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,613,910 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S321L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: DNAJB6 NM_058246.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0700

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-157416079-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.0044648945).
• BP6: Variant 7-157416078-T-C is Benign according to our data. Variant chr7-157416078-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 281947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-157416078-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00145 (220/152228) while in subpopulation AFR AF= 0.00494 (205/41532). AF 95% confidence interval is 0.00438. There are 0 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 220 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJB6	NM_058246.4	c.961T>C	p.Ser321Pro	missense_variant	10/10	ENST00000262177.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJB6	ENST00000262177.9	c.961T>C	p.Ser321Pro	missense_variant	10/10	1	NM_058246.4
DNAJB6	ENST00000459889.5	c.*5484T>C		3_prime_UTR_variant, NMD_transcript_variant	10/10	1
DNAJB6	ENST00000443280.5	c.616T>C	p.Ser206Pro	missense_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152110 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000383 AC: 96 AN: 250350 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135424

Gnomad AFR exome AF: 0.00544

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000166 AC: 242 AN: 1461682 Hom.: 1 Cov.: 32 AF XY: 0.000142 AC XY: 103 AN XY: 727134

Gnomad4 AFR exome AF: 0.00609

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.00145 AC: 220 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.00140 AC XY: 104 AN XY: 74430

Gnomad4 AFR AF: 0.00494

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000287 Hom.: 0

Bravo AF: 0.00174

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000469 AC: 57

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 21, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 14, 2015

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	13
DANN	Benign	0.89
DEOGEN2	Benign	0.39	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.88
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.23
Sift	Uncertain	0.018	D;T
Sift4G	Uncertain	0.010	D;D
Polyphen		0.0	B;B
Vest4		0.071
MVP		0.57
MPC		0.44
ClinPred		0.010	T
GERP RS		-0.86
Varity_R		0.055
gMVP		0.066

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

Other links and lift over

dbSNP: rs147168661; hg19: chr7-157208772;