15-40807388-T-G

Position:

• chr15-40807388-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018163.3(DNAJC17):​c.59A>C​(p.Glu20Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNAJC17 NM_018163.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.36

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]

ZFYVE19 (HGNC:20758): (zinc finger FYVE-type containing 19) Enables phosphatidylinositol-3-phosphate binding activity. Involved in abscission; mitotic cytokinesis checkpoint signaling; and negative regulation of cytokinesis. Located in centrosome; cleavage furrow; and midbody. [provided by Alliance of Genome Resources, Apr 2022]

DNAJC17 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28272635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC17	NM_018163.3	c.59A>C	p.Glu20Ala	missense_variant	1/11	ENST00000220496.9	NP_060633.1
ZFYVE19	NM_001077268.2	c.-202T>G		5_prime_UTR_variant	1/11	ENST00000355341.8	NP_001070736.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJC17	ENST00000220496.9	c.59A>C	p.Glu20Ala	missense_variant	1/11	1	NM_018163.3	ENSP00000220496.4
ZFYVE19	ENST00000355341	c.-202T>G		5_prime_UTR_variant	1/11	1	NM_001077268.2	ENSP00000347498.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with DNAJC17-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 20 of the DNAJC17 protein (p.Glu20Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.053	T;T
Eigen	Benign	0.054
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.17	N;.
PROVEAN	Benign	-0.76	N;.
REVEL	Benign	0.062
Sift	Benign	0.74	T;.
Sift4G	Benign	0.75	T;T
Polyphen		0.0010	B;.
Vest4		0.53
MutPred		0.46		Gain of MoRF binding (P = 0.0471);Gain of MoRF binding (P = 0.0471);
MVP		0.55
MPC		0.30
ClinPred		0.45	T
GERP RS		5.3
Varity_R		0.19
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-41099586;