16-46967633-A-G

Position:

• chr16-46967633-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005880.4(DNAJA2):​c.457T>C​(p.Ser153Pro) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAJA2 NM_005880.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

Genes affected

DNAJA2 (HGNC:14884): (DnaJ heat shock protein family (Hsp40) member A2) The protein encoded by this gene belongs to the evolutionarily conserved DNAJ/HSP40 family of proteins, which regulate molecular chaperone activity by stimulating ATPase activity. DNAJ proteins may have up to 3 distinct domains: a conserved 70-amino acid J domain, usually at the N terminus; a glycine/phenylalanine (G/F)-rich region; and a cysteine-rich domain containing 4 motifs resembling a zinc finger domain. The product of this gene works as a cochaperone of Hsp70s in protein folding and mitochondrial protein import in vitro. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22222883).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJA2	NM_005880.4	c.457T>C	p.Ser153Pro	missense_variant	5/9	ENST00000317089.10	NP_005871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJA2	ENST00000317089.10	c.457T>C	p.Ser153Pro	missense_variant	5/9	1	NM_005880.4	ENSP00000314030.5
DNAJA2	ENST00000617000.1	c.208T>C	p.Ser70Pro	missense_variant	3/4	2		ENSP00000477579.1
DNAJA2	ENST00000563158.1	n.*400T>C		non_coding_transcript_exon_variant	5/9	5		ENSP00000460104.1
DNAJA2	ENST00000563158.1	n.*400T>C		3_prime_UTR_variant	5/9	5		ENSP00000460104.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Mar 01, 2024

The c.457T>C (p.S153P) alteration is located in exon 5 (coding exon 5) of the DNAJA2 gene. This alteration results from a T to C substitution at nucleotide position 457, causing the serine (S) at amino acid position 153 to be replaced by a proline (P). 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	0.067
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.096	T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.17	N;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.37	N;.
REVEL	Benign	0.078
Sift	Benign	0.16	T;.
Sift4G	Benign	0.24	T;.
Polyphen		0.0	B;.
Vest4		0.35
MutPred		0.45		Loss of glycosylation at S153 (P = 0.0416);.;
MVP		0.55
MPC		0.97
ClinPred		0.38	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.066
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr16-47001545;