15-78274276-C-G

Position:

• chr15-78274276-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001130182.2(DNAJA4):​c.498C>G​(p.Ile166Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DNAJA4 NM_001130182.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.81

Genes affected

DNAJA4 (HGNC:14885): (DnaJ heat shock protein family (Hsp40) member A4) Enables chaperone binding activity and unfolded protein binding activity. Involved in several processes, including negative regulation of endothelial cell migration; negative regulation of inclusion body assembly; and protein refolding. Located in cytosol and membrane. [provided by Alliance of Genome Resources, Apr 2022]

DNAJA4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJA4	NM_001130182.2	c.498C>G	p.Ile166Met	missense_variant	4/7	ENST00000394852.8	NP_001123654.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJA4	ENST00000394852.8	c.498C>G	p.Ile166Met	missense_variant	4/7	1	NM_001130182.2	ENSP00000378321.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Apr 15, 2024

The c.585C>G (p.I195M) alteration is located in exon 5 (coding exon 5) of the DNAJA4 gene. This alteration results from a C to G substitution at nucleotide position 585, causing the isoleucine (I) at amino acid position 195 to be replaced by a methionine (M). 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	Benign	0.15
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	.;T;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.93	D;.;D;D
M_CAP	Benign	0.0091	T
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.2	.;L;L;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.40	T;D;D;T
Sift4G	Benign	0.45	T;T;T;T
Polyphen		0.73	P;P;P;.
Vest4		0.64
MutPred		0.52		.;Loss of catalytic residue at P168 (P = 0.0586);Loss of catalytic residue at P168 (P = 0.0586);.;
MVP		0.57
MPC		0.54
ClinPred		0.57	D
GERP RS		-1.7
Varity_R		0.27
gMVP		0.29

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: rs778772507; hg19: chr15-78566618;