chr22-40861069-C-G

Variant names:

• chr22-40861069-C-G
• rs2057941627
• NM_145174.2:c.926G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_145174.2(DNAJB7):​c.926G>C​(p.Cys309Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,426,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAJB7 NM_145174.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.40
• Publications: 0 publications found

Genes affected

DNAJB7 (HGNC:24986): (DnaJ heat shock protein family (Hsp40) member B7) The protein encoded by this intronless 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.[provided by RefSeq, Mar 2011]

XPNPEP3 (HGNC:28052): (X-prolyl aminopeptidase 3) The protein encoded by this gene belongs to the family of X-pro-aminopeptidases that utilize a metal cofactor, and remove the N-terminal amino acid from peptides with a proline residue in the penultimate position. This protein has been shown to localize to the mitochondria of renal cells, and have a role in ciliary function. Mutations in this gene are associated with nephronophthisis-like nephropathy-1. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene, however, expression of some of these isoforms in vivo is not known.[provided by RefSeq, Mar 2011]

XPNPEP3 Gene-Disease associations (from GenCC):

• nephronophthisis-like nephropathy 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• late-onset nephronophthisis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02442959).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145174.2. 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
	DNAJB7	NM_145174.2	MANE Select	c.926G>C	p.Cys309Ser	missense	Exon 1 of 1	NP_660157.1	Q7Z6W7
	XPNPEP3	NM_022098.4	MANE Select	c.64+3824C>G		intron	N/A	NP_071381.1	Q9NQH7-1
	XPNPEP3	NM_001204827.2		c.*12+276C>G		intron	N/A	NP_001191756.1	A0A087X0Z2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB7	ENST00000307221.5	TSL:6 MANE Select	c.926G>C	p.Cys309Ser	missense	Exon 1 of 1	ENSP00000307197.4	Q7Z6W7
	XPNPEP3	ENST00000357137.9	TSL:1 MANE Select	c.64+3824C>G		intron	N/A	ENSP00000349658.4	Q9NQH7-1
	XPNPEP3	ENST00000482652.1	TSL:1	n.265+276C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1426972 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 708034

African (AFR) AF: 0.00 AC: 0 AN: 31610

American (AMR) AF: 0.00 AC: 0 AN: 36420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23852

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39442

South Asian (SAS) AF: 0.00 AC: 0 AN: 79962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098850

Other (OTH) AF: 0.00 AC: 0 AN: 58924

GnomAD4 genome Cov.: 32

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	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.4
DANN	Benign	0.87
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
PhyloP100		-1.4
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.093
Sift	Uncertain	0.017	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.040
MutPred		0.30		Gain of phosphorylation at C309 (P = 0.0012)
MVP		0.28
MPC		0.027
ClinPred		0.21	T
GERP RS		-6.2
Varity_R		0.14
gMVP		0.048
Mutation Taster		=99/1	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: rs2057941627; hg19: chr22-41257073;