Genetic Variant DNAJC8:p.Ala161Thr (chr1-28205340-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_014280.3(DNAJC8):c.481G>A(p.Ala161Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,451,260 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DNAJC8
NM_014280.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

Variant links:

Genes affected

DNAJC8 (HGNC:15470): (DnaJ heat shock protein family (Hsp40) member C8) Enables Hsp70 protein binding activity. Located in cytosol; intercellular bridge; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DNAJC8 links:

Genome browser will be placed here

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
DNAJC8	NM_014280.3 link	c.481G>A	p.Ala161Thr	missense_variant	Exon 7 of 9	ENST00000263697.6	NP_055095.2	O75937
DNAJC8	NR_159454.1 link	n.634G>A		non_coding_transcript_exon_variant	Exon 8 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAJC8	ENST00000263697.6 link	c.481G>A	p.Ala161Thr	missense_variant	Exon 7 of 9	1	NM_014280.3	ENSP00000263697.4	O75937
DNAJC8	ENST00000489277.5 link	n.630G>A		non_coding_transcript_exon_variant	Exon 8 of 10	1		ENSP00000518780.1
DNAJC8	ENST00000603289.5 link	c.10G>A	p.Ala4Thr	missense_variant	Exon 1 of 5	5		ENSP00000474440.2	S4R3J5
DNAJC8	ENST00000470967.1 link	n.478G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000418

AC:

AN:

239058

Hom.:

AF XY:

0.00000772

AC XY:

AN XY:

129596

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000906

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1451260

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721774

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.481G>A (p.A161T) alteration is located in exon 7 (coding exon 7) of the DNAJC8 gene. This alteration results from a G to A substitution at nucleotide position 481, causing the alanine (A) at amino acid position 161 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

0.22

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.040

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.065

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.9

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.2

REVEL

Benign

0.25

Sift

Benign

0.091

Sift4G

Benign

0.38

Polyphen

0.80

Vest4

0.77

MutPred

0.17

Gain of phosphorylation at A161 (P = 0.0248);

MVP

0.70

MPC

1.7

ClinPred

0.80

GERP RS

5.6

Varity_R

0.24

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over