NM_152686.4:c.629G>A

Variant names:

• chr5-139425045-C-T
• rs772188857
• NM_152686.4:c.629G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152686.4(DNAJC18):​c.629G>A​(p.Arg210Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DNAJC18 NM_152686.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16
• Publications: 0 publications found

Genes affected

DNAJC18 (HGNC:28429): (DnaJ heat shock protein family (Hsp40) member C18) Predicted to enable Hsp70 protein binding activity. Predicted to be involved in cellular response to misfolded protein; chaperone cofactor-dependent protein refolding; and ubiquitin-dependent ERAD pathway. Predicted to be integral component of membrane. Predicted to be active in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14295426).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152686.4. 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
	DNAJC18	NM_152686.4	MANE Select	c.629G>A	p.Arg210Lys	missense	Exon 5 of 8	NP_689899.1	Q9H819

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC18	ENST00000302060.10	TSL:1 MANE Select	c.629G>A	p.Arg210Lys	missense	Exon 5 of 8	ENSP00000302843.5	Q9H819
	DNAJC18	ENST00000928618.1		c.656G>A	p.Arg219Lys	missense	Exon 6 of 9	ENSP00000598677.1
	DNAJC18	ENST00000886188.1		c.599G>A	p.Arg200Lys	missense	Exon 5 of 8	ENSP00000556247.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151954 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251438 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461228 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726930

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111508

Other (OTH) AF: 0.00 AC: 0 AN: 60352

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000147827), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151954 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74196

African (AFR) AF: 0.00 AC: 0 AN: 41362

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

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	0.081
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.058
Eigen_PC	Benign	-0.017
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.2
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.15
Sift	Uncertain	0.023	D
Sift4G	Benign	0.12	T
Polyphen		0.61	P
Vest4		0.31
MutPred		0.36		Gain of methylation at R210 (P = 0.0071)
MVP		0.70
MPC		0.39
ClinPred		0.27	T
GERP RS		3.9
PromoterAI		0.028	Neutral
Varity_R		0.11
gMVP		0.85
Mutation Taster		=95/5	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: rs772188857; hg19: chr5-138760734;