dbSNP rs201565517: DNAJB4:p.Pro270Thr (chr1-78016041-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007034.5(DNAJB4):c.808C>A(p.Pro270Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P270S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DNAJB4
NM_007034.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.67

Variant links:

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]

DNAJB4 links:

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]

GIPC2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJB4	NM_007034.5 link	c.808C>A	p.Pro270Thr	missense_variant	Exon 3 of 3	ENST00000370763.6	NP_008965.2	Q9UDY4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAJB4	ENST00000370763.6 link	c.808C>A	p.Pro270Thr	missense_variant	Exon 3 of 3	1	NM_007034.5	ENSP00000359799.5	Q9UDY4
DNAJB4	ENST00000476396.1 link	n.415C>A		non_coding_transcript_exon_variant	Exon 2 of 2	3
DNAJB4	ENST00000487931.1 link	n.716C>A		non_coding_transcript_exon_variant	Exon 3 of 3	2
GIPC2	ENST00000476882.1 link	n.78+36422C>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461746

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-7.3

REVEL

Benign

0.28

Sift

Benign

0.11

Sift4G

Benign

0.15

Polyphen

0.86

Vest4

0.47

MutPred

0.71

Loss of stability (P = 0.1009);

MVP

0.33

MPC

0.24

ClinPred

0.97

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.51

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over