chr9-111649894-C-G

Variant names:

• chr9-111649894-C-G
• rs749436855
• NM_001015882.3:c.931C>G

Variant summary

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

The NM_001015882.3(DNAJC25):​c.931C>G​(p.Arg311Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000879 in 1,593,122 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: DNAJC25 NM_001015882.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39
• Publications: 0 publications found

Genes affected

DNAJC25 (HGNC:34187): (DnaJ heat shock protein family (Hsp40) member C25) Predicted to be involved in protein folding. Predicted to be located in membrane. Predicted to be integral component of membrane. Predicted to be active in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

DNAJC25-GNG10 (HGNC:37501): (DNAJC25-GNG10 readthrough) This gene represents naturally-occurring mRNAs that are co-transcribed products of the neighboring DNAJC25 and GNG10 genes. These transcripts include the first exon of DNAJC25 and the last two exons of GNG10, resulting in a protein that combines the N-terminus of DNAJC25 and the C-terminus of GNG10. [provided by RefSeq, Dec 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001015882.3. 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
	DNAJC25	NM_001015882.3	MANE Select	c.931C>G	p.Arg311Gly	missense	Exon 3 of 4	NP_001015882.2	Q9H1X3-1
	DNAJC25-GNG10	NM_004125.4		c.337-16921C>G		intron	N/A	NP_004116.2
	DNAJC25	NR_037148.2		n.1243C>G		non_coding_transcript_exon	Exon 4 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC25	ENST00000313525.4	TSL:1 MANE Select	c.931C>G	p.Arg311Gly	missense	Exon 3 of 4	ENSP00000320650.3	Q9H1X3-1
	DNAJC25-GNG10	ENST00000374294.3	TSL:2	c.337-16921C>G		intron	N/A	ENSP00000363412.3
	DNAJC25	ENST00000447096.1	TSL:1	n.*761C>G		non_coding_transcript_exon	Exon 4 of 5	ENSP00000399325.1	F2Z3D1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000349 AC: 8 AN: 229516 AF XY: 0.0000321

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: 0.0000977

Gnomad NFE exome AF: 0.0000472

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000833 AC: 12 AN: 1441020 Hom.: 0 Cov.: 32 AF XY: 0.00000977 AC XY: 7 AN XY: 716142

African (AFR) AF: 0.00 AC: 0 AN: 32244

American (AMR) AF: 0.00 AC: 0 AN: 40840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24850

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82096

European-Finnish (FIN) AF: 0.0000381 AC: 2 AN: 52552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4322

European-Non Finnish (NFE) AF: 0.00000814 AC: 9 AN: 1105210

Other (OTH) AF: 0.00 AC: 0 AN: 59322

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74290

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

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.000131 AC: 2 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000414 AC: 5

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	-0.18	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.4
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.16
Sift	Benign	0.072	T
Sift4G	Benign	0.15	T
Polyphen		0.93	P
Vest4		0.72
MutPred		0.36		Loss of methylation at K310 (P = 0.0478)
MVP		0.70
MPC		0.32
ClinPred		0.27	T
GERP RS		3.9
Varity_R		0.48
gMVP		0.42
Mutation Taster		=65/35	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: rs749436855; hg19: chr9-114412174;