1-78005267-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_007034.5(DNAJB4):c.157G>A(p.Glu53Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAJB4 NM_007034.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

Genes affected

DNAJB4 (HGNC:14886): (DnaJ heat shock protein family (Hsp40) member B4) The protein encoded by this gene is a molecular chaperone, tumor suppressor, and member of the heat shock protein-40 family. The encoded protein binds the cell adhesion protein E-cadherin and targets it to the plasma membrane. This protein also binds incorrectly folded E-cadherin and targets it for endoplasmic reticulum-associated degradation. This gene is a strong tumor suppressor for colorectal carcinoma, and downregulation of it may serve as a good biomarker for predicting patient outcomes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

GIPC2 (HGNC:18177): (GIPC PDZ domain containing family member 2) Enables identical protein binding activity. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJB4	NM_007034.5	c.157G>A	p.Glu53Lys	missense_variant	1/3	ENST00000370763.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJB4	ENST00000370763.6	c.157G>A	p.Glu53Lys	missense_variant	1/3	1	NM_007034.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Dec 15, 2022

The c.157G>A (p.E53K) alteration is located in exon 1 (coding exon 1) of the DNAJB4 gene. This alteration results from a G to A substitution at nucleotide position 157, causing the glutamic acid (E) at amino acid position 53 to be replaced by a lysine (K). 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.033	D;D
Polyphen		0.88	.;P
Vest4		0.64
MutPred		0.69		Gain of methylation at E53 (P = 0.0083);Gain of methylation at E53 (P = 0.0083);
MVP		0.64
MPC		0.62
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.65
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-78470951;