22-40861627-G-A

Position:

• chr22-40861627-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_145174.2(DNAJB7):​c.368C>T​(p.Pro123Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,613,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: DNAJB7 NM_145174.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.226

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045874238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJB7	NM_145174.2	c.368C>T	p.Pro123Leu	missense_variant	1/1	ENST00000307221.5	NP_660157.1
XPNPEP3	NM_022098.4	c.64+4382G>A		intron_variant		ENST00000357137.9	NP_071381.1
XPNPEP3	NM_001204827.2	c.*22G>A		3_prime_UTR_variant	3/3		NP_001191756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJB7	ENST00000307221.5	c.368C>T	p.Pro123Leu	missense_variant	1/1	6	NM_145174.2	ENSP00000307197.4
XPNPEP3	ENST00000357137.9	c.64+4382G>A		intron_variant		1	NM_022098.4	ENSP00000349658.4

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000228 AC: 57 AN: 249824 Hom.: 0 AF XY: 0.000251 AC XY: 34 AN XY: 135268

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000428

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000363

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000301 AC: 440 AN: 1461326 Hom.: 0 Cov.: 31 AF XY: 0.000297 AC XY: 216 AN XY: 726952

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000476

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000340

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74442

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000390 Hom.: 1

Bravo AF: 0.000212

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000436

EpiControl AF: 0.000593

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

Mar 14, 2023

The c.368C>T (p.P123L) alteration is located in exon 1 (coding exon 1) of the DNAJB7 gene. This alteration results from a C to T substitution at nucleotide position 368, causing the proline (P) at amino acid position 123 to be replaced by a leucine (L). 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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	6.0
DANN	Benign	0.48
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	2.0	M
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.15
Sift	Benign	0.37	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.27
MVP		0.68
MPC		0.030
ClinPred		0.015	T
GERP RS		2.6
Varity_R		0.055
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: rs191614236; hg19: chr22-41257631;