chr2-24957932-C-A

Position:

• chr2-24957932-C-A

Variant summary

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

The NM_016544.3(DNAJC27):​c.283G>T​(p.Val95Phe) variant causes a missense change involving the alteration of a 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: 32)
• Consequence: DNAJC27 NM_016544.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.65

Genes affected

DNAJC27 (HGNC:30290): (DnaJ heat shock protein family (Hsp40) member C27) Predicted to enable GTPase activity. Predicted to be involved in intracellular protein transport and positive regulation of MAPK cascade. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC27	NM_016544.3	c.283G>T	p.Val95Phe	missense_variant	4/7	ENST00000264711.7	NP_057628.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJC27	ENST00000264711.7	c.283G>T	p.Val95Phe	missense_variant	4/7	1	NM_016544.3	ENSP00000264711	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Ambry Genetics

Oct 27, 2023

The c.283G>T (p.V95F) alteration is located in exon 4 (coding exon 4) of the DNAJC27 gene. This alteration results from a G to T substitution at nucleotide position 283, causing the valine (V) at amino acid position 95 to be replaced by a phenylalanine (F). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.6	D;.
REVEL	Pathogenic	0.90
Sift	Benign	0.045	D;.
Sift4G	Uncertain	0.022	D;D
Polyphen		0.95	P;B
Vest4		0.93
MutPred		0.59		Gain of catalytic residue at V95 (P = 0.0613);Gain of catalytic residue at V95 (P = 0.0613);
MVP		0.92
MPC		0.77
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.54
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1665947522; hg19: chr2-25180801;