NM_003315.4:c.1423G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003315.4(DNAJC7):c.1423G>A(p.Gly475Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000126 in 1,585,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

DNAJC7
NM_003315.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.70

Publications

1 publications found

Variant links:

Genes affected

DNAJC7 (HGNC:12392): (DnaJ heat shock protein family (Hsp40) member C7) This gene encodes a member of the DNAJ heat shock protein 40 family of proteins that is characterized by two N-terminal tetratricopeptide repeat domains and a C-terminal DNAJ domain. This protein binds the chaperone proteins heat shock proteins 70 and 90 in an ATP-dependent manner and may function as a co-chaperone. Pseudogenes of this gene are found on chromosomes 1 and 6. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2009]

DNAJC7 links:

CNP (HGNC:2158): (2',3'-cyclic nucleotide 3' phosphodiesterase) Predicted to enable 2',3'-cyclic-nucleotide 3'-phosphodiesterase activity. Involved in substantia nigra development. Located in several cellular components, including extracellular space; microtubule; and plasma membrane. Implicated in hypomyelinating leukodystrophy 20; multiple sclerosis; and schizophrenia. Biomarker of alcoholic liver cirrhosis; multiple sclerosis; and restless legs syndrome. [provided by Alliance of Genome Resources, Apr 2022]

CNP Gene-Disease associations (from GenCC):

leukodystrophy, hypomyelinating, 20
Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

CNP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25806975).

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC7	NM_003315.4 link	c.1423G>A	p.Gly475Ser	missense_variant	Exon 13 of 14	ENST00000457167.9	NP_003306.3	Q99615-1
CNP	NM_033133.5 link	c.*3361C>T		3_prime_UTR_variant	Exon 4 of 4	ENST00000393892.8	NP_149124.3	P09543-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC7	ENST00000457167.9 link	c.1423G>A	p.Gly475Ser	missense_variant	Exon 13 of 14	1	NM_003315.4	ENSP00000406463.2		Q99615-1
CNP	ENST00000393892.8 link	c.*3361C>T		3_prime_UTR_variant	Exon 4 of 4	1	NM_033133.5	ENSP00000377470.2		P09543-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000968

AC:

AN:

206522

AF XY:

0.00000903

show subpopulations

Gnomad AFR exome

AF:

0.0000825

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000119

AC:

AN:

1433102

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

710042

show subpopulations

African (AFR)

AF:

0.0000305

AC:

AN:

32830

American (AMR)

AF:

0.00

AC:

AN:

40076

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25594

East Asian (EAS)

AF:

0.0000261

AC:

AN:

38282

South Asian (SAS)

AF:

0.0000368

AC:

AN:

81604

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51634

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0000100

AC:

AN:

1097880

Other (OTH)

AF:

0.0000168

AC:

AN:

59454

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1423G>A (p.G475S) alteration is located in exon 13 (coding exon 13) of the DNAJC7 gene. This alteration results from a G to A substitution at nucleotide position 1423, causing the glycine (G) at amino acid position 475 to be replaced by a serine (S). 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

0.081

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.24

T;T;.;.

Eigen

Benign

0.064

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;D;.;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.8

L;.;.;.

PhyloP100

5.7

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.2

N;.;N;N

REVEL

Benign

0.20

Sift

Benign

0.33

T;.;T;T

Sift4G

Benign

0.098

T;T;T;T

Polyphen

0.11

B;.;.;.

Vest4

0.56

MutPred

0.42

Gain of glycosylation at G475 (P = 0.0046);.;.;.;

MVP

0.64

MPC

0.62

ClinPred

0.32

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.73

Mutation Taster

=54/46

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over