15-40807393-A-C

Position:

• chr15-40807393-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000220496.9(DNAJC17):​c.54T>G​(p.Ile18Met) variant causes a missense change involving the alteration of a non-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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAJC17 ENST00000220496.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0580

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC17	NM_018163.3	c.54T>G	p.Ile18Met	missense_variant	1/11	ENST00000220496.9	NP_060633.1
ZFYVE19	NM_001077268.2	c.-197A>C		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.54T>G	p.Ile18Met	missense_variant	1/11	1	NM_018163.3	ENSP00000220496.4
ZFYVE19	ENST00000355341	c.-197A>C		5_prime_UTR_variant	1/11	1	NM_001077268.2	ENSP00000347498.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Feb 20, 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 18 of the DNAJC17 protein (p.Ile18Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;T
Eigen	Benign	0.14
Eigen_PC	Benign	-0.017
FATHMM_MKL	Benign	0.50	N
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.7	N;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.012	D;D
Polyphen		0.98	D;.
Vest4		0.55
MutPred		0.81		Gain of disorder (P = 0.004);Gain of disorder (P = 0.004);
MVP		0.37
MPC		0.78
ClinPred		0.98	D
GERP RS		-3.0
Varity_R		0.48
gMVP		0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-41099591;