4-99906521-C-T

Variant names:

• chr4-99906521-C-T
• rs764504479
• NM_001031723.4:c.728G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001031723.4(DNAJB14):​c.728G>A​(p.Gly243Glu) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G243R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAJB14 NM_001031723.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27
• Publications: 2 publications found

Genes affected

DNAJB14 (HGNC:25881): (DnaJ heat shock protein family (Hsp40) member B14) Enables Hsp70 protein binding activity. Involved in cellular protein-containing complex assembly and chaperone cofactor-dependent protein refolding. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000299569 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27590775).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031723.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB14	NM_001031723.4	MANE Select	c.728G>A	p.Gly243Glu	missense	Exon 5 of 8	NP_001026893.1	Q8TBM8-1
	DNAJB14	NM_001278310.2		c.527G>A	p.Gly176Glu	missense	Exon 4 of 7	NP_001265239.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB14	ENST00000442697.7	TSL:1 MANE Select	c.728G>A	p.Gly243Glu	missense	Exon 5 of 8	ENSP00000404381.2	Q8TBM8-1
	DNAJB14	ENST00000334223.6	TSL:1	n.*418G>A		non_coding_transcript_exon	Exon 4 of 7	ENSP00000335249.2	F2Z2L8
	DNAJB14	ENST00000420137.5	TSL:1	n.*616G>A		non_coding_transcript_exon	Exon 7 of 10	ENSP00000416179.1	H7C494

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250720 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.86e-7 AC: 1 AN: 1458718 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725668

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4142

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111358

Other (OTH) AF: 0.00 AC: 0 AN: 60170

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.15
Sift	Benign	0.21	T
Sift4G	Benign	0.78	T
Polyphen		0.0010	B
Vest4		0.58
MutPred		0.28		Gain of solvent accessibility (P = 0.024)
MVP		0.40
MPC		1.3
ClinPred		0.78	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.84
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs764504479; hg19: chr4-100827678;