chr15-40767999-C-G

Position:

• chr15-40767999-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018163.3(DNAJC17):​c.856G>C​(p.Glu286Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00119 in 1,605,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: DNAJC17 NM_018163.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.44

Genes affected

DNAJC17 (HGNC:25556): (DnaJ heat shock protein family (Hsp40) member C17) Predicted to enable RNA binding activity. Predicted to act upstream of or within negative regulation of transcription by RNA polymerase II and toxin transport. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

DNAJC17 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06540269).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC17	NM_018163.3	c.856G>C	p.Glu286Gln	missense_variant	11/11	ENST00000220496.9	NP_060633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJC17	ENST00000220496.9	c.856G>C	p.Glu286Gln	missense_variant	11/11	1	NM_018163.3	ENSP00000220496.4

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000651 AC: 157 AN: 241194 Hom.: 0 AF XY: 0.000618 AC XY: 81 AN XY: 131050

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.000187

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000478

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.000858

GnomAD4 exome AF: 0.00124 AC: 1799 AN: 1453566 Hom.: 0 Cov.: 33 AF XY: 0.00119 AC XY: 862 AN XY: 723348

Gnomad4 AFR exome AF: 0.000336

Gnomad4 AMR exome AF: 0.000355

Gnomad4 ASJ exome AF: 0.0000388

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.000190

Gnomad4 NFE exome AF: 0.00155

Gnomad4 OTH exome AF: 0.000684

GnomAD4 genome AF: 0.000722 AC: 110 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000644 AC XY: 48 AN XY: 74478

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000431 Hom.: 0

Bravo AF: 0.000710

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000717 AC: 87

EpiCase AF: 0.00120

EpiControl AF: 0.00155

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 286 of the DNAJC17 protein (p.Glu286Gln). This variant is present in population databases (rs142251536, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DNAJC17-related conditions. ClinVar contains an entry for this variant (Variation ID: 1361751). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.856G>C (p.E286Q) alteration is located in exon 11 (coding exon 11) of the DNAJC17 gene. This alteration results from a G to C substitution at nucleotide position 856, causing the glutamic acid (E) at amino acid position 286 to be replaced by a glutamine (Q). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.012	D
Polyphen		0.99	D
Vest4		0.43
MVP		0.53
MPC		0.82
ClinPred		0.15	T
GERP RS		5.7
Varity_R		0.39
gMVP		0.64

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: rs142251536; hg19: chr15-41060197;