19-14515975-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006145.3(DNAJB1):c.988T>A(p.Ser330Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000301 in 1,609,574 control chromosomes in the GnomAD database, including 2 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: DNAJB1 NM_006145.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.59

Genes affected

DNAJB1 (HGNC:5270): (DnaJ heat shock protein family (Hsp40) member B1) This gene encodes a member of the DnaJ or Hsp40 (heat shock protein 40 kD) family of proteins. 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. The encoded protein is a molecular chaperone that stimulates the ATPase activity of Hsp70 heat-shock proteins in order to promote protein folding and prevent misfolded protein aggregation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050275117).
• BS2: High AC in GnomAd at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJB1	NM_006145.3	c.988T>A	p.Ser330Thr	missense_variant	3/3	ENST00000254322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJB1	ENST00000254322.3	c.988T>A	p.Ser330Thr	missense_variant	3/3	1	NM_006145.3	P1

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 151816 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000242 AC: 60 AN: 247964 Hom.: 1 AF XY: 0.000238 AC XY: 32 AN XY: 134360

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000213

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000656

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000275

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000314 AC: 458 AN: 1457640 Hom.: 1 Cov.: 31 AF XY: 0.000317 AC XY: 230 AN XY: 725416

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.000163

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000570

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000346

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000178 AC: 27 AN: 151934 Hom.: 1 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74280

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000309 Hom.: 0

Bravo AF: 0.000208

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000313 AC: 38

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2023

The c.988T>A (p.S330T) alteration is located in exon 3 (coding exon 3) of the DNAJB1 gene. This alteration results from a T to A substitution at nucleotide position 988, causing the serine (S) at amino acid position 330 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	18
Dann	Benign	0.87
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.70	N;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.51	N;N
REVEL	Benign	0.099
Sift	Benign	0.67	T;T
Sift4G	Benign	0.64	T;T
Polyphen		0.0020	B;.
Vest4		0.30
MVP		0.45
MPC		0.22
ClinPred		0.022	T
GERP RS		5.1
Varity_R		0.19
gMVP		0.67

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: rs138234955; hg19: chr19-14626787;