Variant 7-73683191-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_032317.3(DNAJC30):c.233C>G(p.Pro78Arg) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P78S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DNAJC30
NM_032317.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.34

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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC30	NM_032317.3 linkuse as main transcript	c.233C>G	p.Pro78Arg	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.233C>G	p.Pro78Arg	missense_variant	1/1	6	NM_032317.3	ENSP00000378605.1		Q96LL9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249542

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135354

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.84e-7

AC:

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727202

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Leber-like hereditary optic neuropathy, autosomal recessive 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Jun 10, 2024

The c.233C>G variants are not present in publicly available population databases like 1000 Genomes, EVS, Indian Exome Database or our in-house exome database. This variant is present in ExAC and gnomAD at low frequencies. This variant has neither been published in literature with DNAJC30-related conditions nor reported to clinical databases like ClinVar, Human Genome Mutation Database (HGMD) or OMIM, in any affected individuals. In-silico pathogenicity programs like SIFT, PolyPhen-2, MutationTaster2, CADD etc predicted this variant to be likely deleterious, however these predictions were not confirmed by published functional studies. A different amino acid change in the same codon (Pro78Ser) has been previously observed in affected individuals [PMID: 33465056] and reported to the clinical databases as ‘Pathogenic’. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-9.0

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.92

MutPred

0.91

Gain of MoRF binding (P = 0.0412);

MVP

0.93

MPC

1.3

ClinPred

1.0

GERP RS

5.1

Varity_R

0.84

gMVP

0.74

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