7-73683272-T-C

Position:

chr7-73683272-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM1PP3PP5_Very_StrongBP4

The NM_032317.3(DNAJC30):c.152A>G(p.Tyr51Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000755 in 1,614,068 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0011 ( 3 hom., cov: 34)

Exomes 𝑓: 0.00072 ( 2 hom. )

Consequence

DNAJC30
NM_032317.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 6.72

Variant links:

Genes affected

DNAJC30 (HGNC:16410): (DnaJ heat shock protein family (Hsp40) member C30) This intronless gene encodes a member of the DNAJ molecular chaperone homology domain-containing protein family. This gene is deleted in Williams syndrome, a multisystem developmental disorder caused by the deletion of contiguous genes at 7q11.23. [provided by RefSeq, Jul 2008]

DNAJC30 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a domain J (size 65) in uniprot entity DJC30_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_032317.3

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 7-73683272-T-C is Pathogenic according to our data. Variant chr7-73683272-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 976691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-73683272-T-C is described in Lovd as [Pathogenic]. Variant chr7-73683272-T-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.4235457). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC30	NM_032317.3 linkuse as main transcript	c.152A>G	p.Tyr51Cys	missense_variant	1/1	ENST00000395176.3	NP_115693.2	Q96LL9B3KSU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJC30	ENST00000395176.3 linkuse as main transcript	c.152A>G	p.Tyr51Cys	missense_variant	1/1	6	NM_032317.3	ENSP00000378605.1		Q96LL9

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

167

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00160

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00112

AC:

280

AN:

249740

Hom.:

AF XY:

0.00107

AC XY:

145

AN XY:

135414

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00339

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00479

Gnomad NFE exome

AF:

0.00121

Gnomad OTH exome

AF:

0.000983

GnomAD4 exome

AF:

0.000720

AC:

1052

AN:

1461714

Hom.:

Cov.:

AF XY:

0.000784

AC XY:

570

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00279

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00460

Gnomad4 NFE exome

AF:

0.000620

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.00110

AC:

167

AN:

152354

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00471

Gnomad4 NFE

AF:

0.00160

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00127

Hom.:

Bravo

AF:

0.000646

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000931

AC:

ExAC

AF:

0.000873

AC:

106

EpiCase

AF:

0.00115

EpiControl

AF:

0.000652

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leber hereditary optic neuropathy, autosomal recessive

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Personalized Medicine Clinic, Tartu University Hospital	Jul 10, 2023	Observed in two unrelated cases in homozygosity, both had the clinical diagnosis of LHON. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 05, 2021	PS3, PM1, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.125%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.47). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000976691). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 33465056). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2023	Observed in homozygous state in patients with Leber hereditary optic neuropathy, optic atrophy, or Leigh syndrome and in asymptomatic individuals in the published literature (Stenton et al., 2021, Kieninger et al., 2022; Stenton et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36388184, 35148383, 35091433, 33465056, 36674591, 36359543, 35861300, 36294366) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -

DNAJC30-associated disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Nov 06, 2019

- -

Optic atrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2023

- -

Leber optic atrophy, susceptibility to

Pathogenic:1

Pathogenic, criteria provided, single submitter

not provided

Institute of Human Genetics, University Hospital of Duesseldorf

- -

Leber-like hereditary optic neuropathy, autosomal recessive 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 09, 2024

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.42

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.42

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

4.3

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-8.6

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MVP

0.89

MPC

1.4

ClinPred

0.37

GERP RS

5.3

Varity_R

0.82

gMVP

0.75

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

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