10-67797189-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_021800.3(DNAJC12):c.524G>A(p.Trp175*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000973 in 1,613,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

DNAJC12
NM_021800.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.86

Variant links:

Genes affected

DNAJC12 (HGNC:28908): (DnaJ heat shock protein family (Hsp40) member C12) This gene encodes a member of a subclass of the HSP40/DnaJ protein family. Members of this family of proteins are associated with complex assembly, protein folding, and export. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

DNAJC12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.122 CDS is truncated, and there are 3 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-67797189-C-T is Pathogenic according to our data. Variant chr10-67797189-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 870655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-67797189-C-T is described in Lovd as [Pathogenic]. Variant chr10-67797189-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC12	NM_021800.3 link	c.524G>A	p.Trp175*	stop_gained	Exon 5 of 5	ENST00000225171.7	NP_068572.1	Q9UKB3-1Q6IAH1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC12	ENST00000225171.7 link	c.524G>A	p.Trp175*	stop_gained	Exon 5 of 5	1	NM_021800.3	ENSP00000225171.2		Q9UKB3-1
DNAJC12	ENST00000483798.6 link	c.614G>A	p.Trp205*	stop_gained	Exon 6 of 6	3		ENSP00000474215.1		S4R3E2

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000172

AC:

AN:

250564

Hom.:

AF XY:

0.000192

AC XY:

AN XY:

135592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000958

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000707

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000842

AC:

123

AN:

1461390

Hom.:

Cov.:

AF XY:

0.0000784

AC XY:

AN XY:

726956

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000223

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000103

Hom.:

Bravo

AF:

0.000261

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperphenylalaninemia due to DNAJC12 deficiency

Pathogenic:4

Apr 14, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 12, 2020

Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 22, 2021

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DNAJC12 c.524G>A (p.Trp175X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, however, nonsense mediated decay is not expected to occur. The variant allele was found at a frequency of 0.00017 in 250564 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DNAJC12 causing Hyperphenylalaninemia Due To DNAJC12 Deficiency, allowing no conclusion about variant significance. c.524G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Hyperphenylalaninemia Due To DNAJC12 Deficiency (e.g. Gallego_2020, Navarette_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing the variant results reduced PAH protein levels and activity, suggesting an inability of DNAJC12 to contribute to the PAH folding process (e.g. Gallego_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32333439, 30626930).ClinVar contains an entry for this variant (Variation ID: 870655). Based on the evidence outlined above, the variant was classified as pathogenic. -

DNAJC12-related disorder

Pathogenic:1

Jun 13, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DNAJC12 c.524G>A variant is predicted to result in premature protein termination (p.Trp175*). This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with hyperphenylalaninaemia (Navarrete et al 2019. PubMed ID: 30626930; Gallego D et al 2020. PubMed ID: 32333439). This variant is reported in 0.093% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-69556947-C-T). Nonsense variants in DNAJC12 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Jul 30, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.524G>A (p.W175*) alteration, located in exon 5 (coding exon 5) of the DNAJC12 gene, consists of a G to A substitution at nucleotide position 524. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 175. This alteration occurs at the 3' terminus of the DNAJC12 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 12.2% (24/198 amino acids) of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been detected in the homozygous and compound heterozygous states in multiple individuals with hyperphenylalaninemia (HPA) (Gallego, 2020). Functional studies on fibroblasts showed reduced amounts of PAH and PAH activity affecting the PAH folding process. Steady-state tyrosine hydroxylase levels were also reduced while tryptophan hydroxylase 2 levels were not affected (Gallego, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

not provided

Pathogenic:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp175*) in the DNAJC12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the DNAJC12 protein. This variant is present in population databases (rs370032864, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with hyperphenylalaninemia (PMID: 30626930, 32333439). ClinVar contains an entry for this variant (Variation ID: 870655). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects DNAJC12 function (PMID: 32333439). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.81

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.87

Vest4

0.24

GERP RS

5.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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