10-72354954-C-G

Position:

• chr10-72354954-C-G

Variant summary

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

The ENST00000394903.6(DNAJB12):​c.46G>C​(p.Ala16Pro) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAJB12 ENST00000394903.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

Genes affected

DNAJB12 (HGNC:14891): (DnaJ heat shock protein family (Hsp40) member B12) DNAJB12 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 (Ohtsuka and Hata, 2000 [PubMed 11147971]).[supplied by OMIM, Mar 2008]

(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=0.36897385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJB12	NM_017626.7	c.-57G>C		upstream_gene_variant		ENST00000444643.8	NP_060096.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJB12	ENST00000394903.6	c.46G>C	p.Ala16Pro	missense_variant	1/9	1		ENSP00000378363.2
DNAJB12	ENST00000338820.7	c.46G>C	p.Ala16Pro	missense_variant	1/8	2		ENSP00000345575.3
DNAJB12	ENST00000444643.8	c.-57G>C		upstream_gene_variant		1	NM_017626.7	ENSP00000403313.2

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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The c.46G>C (p.A16P) alteration is located in exon 1 (coding exon 1) of the DNAJB12 gene. This alteration results from a G to C substitution at nucleotide position 46, causing the alanine (A) at amino acid position 16 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
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0075	T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.52	.;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	-0.25	T
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.15	N;N
REVEL	Benign	0.11
Sift	Benign	0.071	T;T
Sift4G	Pathogenic	0.0	D;D
Vest4		0.45
MutPred		0.19		Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);
MVP		0.81
MPC		1.2
ClinPred		0.98	D
GERP RS		5.6
gMVP		0.37

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: rs1264436192; hg19: chr10-74114712;