13-95723254-A-G

Position:

• chr13-95723254-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_006260.5(DNAJC3):​c.206A>G​(p.Asp69Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00049 in 1,597,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. D69E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: DNAJC3 NM_006260.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.54

Genes affected

DNAJC3 (HGNC:9439): (DnaJ heat shock protein family (Hsp40) member C3) This gene encodes a protein with multiple tetratricopeptide repeat (TPR) motifs as well as the highly conserved J domain found in DNAJ chaperone family members. It is a member of the tetratricopeptide repeat family of proteins and acts as an inhibitor of the interferon-induced, dsRNA-activated protein kinase (PKR). [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.113149345).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000499 (76/152286) while in subpopulation NFE AF= 0.000853 (58/68024). AF 95% confidence interval is 0.000677. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC3	NM_006260.5	c.206A>G	p.Asp69Gly	missense_variant	3/12	ENST00000602402.6	NP_006251.1
DNAJC3	XM_011521104.3	c.206A>G	p.Asp69Gly	missense_variant	3/13		XP_011519406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJC3	ENST00000602402.6	c.206A>G	p.Asp69Gly	missense_variant	3/12	1	NM_006260.5	ENSP00000473631	P1
DNAJC3	ENST00000376795.6	c.206A>G	p.Asp69Gly	missense_variant	3/11	5		ENSP00000365991

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152168 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000389 AC: 96 AN: 246616 Hom.: 0 AF XY: 0.000345 AC XY: 46 AN XY: 133164

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000211

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000137

Gnomad FIN exome AF: 0.000787

Gnomad NFE exome AF: 0.000560

Gnomad OTH exome AF: 0.000666

GnomAD4 exome AF: 0.000489 AC: 707 AN: 1445000 Hom.: 0 Cov.: 30 AF XY: 0.000448 AC XY: 322 AN XY: 718180

Gnomad4 AFR exome AF: 0.0000604

Gnomad4 AMR exome AF: 0.000300

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000720

Gnomad4 FIN exome AF: 0.00102

Gnomad4 NFE exome AF: 0.000543

Gnomad4 OTH exome AF: 0.000437

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152286 Hom.: 0 Cov.: 31 AF XY: 0.000483 AC XY: 36 AN XY: 74466

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000612 Hom.: 0

Bravo AF: 0.000359

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000362 AC: 44

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.5	.;N
REVEL	Benign	0.16
Sift	Benign	0.050	.;D
Sift4G	Benign	0.14	T;T
Polyphen		0.095	B;.
Vest4		0.49
MVP		0.51
MPC		0.61
ClinPred		0.038	T
GERP RS		5.8
Varity_R		0.27
gMVP		0.66

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

Other links and lift over

dbSNP: rs148990795; hg19: chr13-96375508; COSMIC: COSV99060785;