7-73683020-G-A

Position:

• chr7-73683020-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_032317.3(DNAJC30):​c.404C>T​(p.Pro135Leu) 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. 14/21 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. P135S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: DNAJC30 NM_032317.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

Genes affected

DNAJC30 (HGNC:16410): (DnaJ heat shock protein family (Hsp40) member C30) This intronless gene encodes a member of the DNAJ molecular chaperone homology domain-containing protein family. This gene is deleted in Williams syndrome, a multisystem developmental disorder caused by the deletion of contiguous genes at 7q11.23. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain DnaJ homolog subfamily C member 30, mitochondrial (size 187) in uniprot entity DJC30_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in NM_032317.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10341734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJC30	NM_032317.3	c.404C>T	p.Pro135Leu	missense_variant	1/1	ENST00000395176.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJC30	ENST00000395176.3	c.404C>T	p.Pro135Leu	missense_variant	1/1		NM_032317.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 53

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000113

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

Dec 11, 2023

The c.404C>T (p.P135L) alteration is located in exon 1 (coding exon 1) of the DNAJC30 gene. This alteration results from a C to T substitution at nucleotide position 404, causing the proline (P) at amino acid position 135 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	0.087
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.060
Sift	Benign	0.039	D
Sift4G	Benign	0.16	T
Polyphen		0.068	B
Vest4		0.17
MutPred		0.28		Loss of loop (P = 0.0288);
MVP		0.41
MPC		0.48
ClinPred		0.096	T
GERP RS		2.3
Varity_R		0.034
gMVP		0.41

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: rs1797765304; hg19: chr7-73097350;