10-67797180-C-G

Variant names:

• chr10-67797180-C-G
• rs764261610
• NM_021800.3:c.533G>C

Variant summary

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

The NM_021800.3(DNAJC12):​c.533G>C​(p.Arg178Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,378 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNAJC12 NM_021800.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.14
• Publications: 1 publications found

Genes affected

DNAJC12 (HGNC:28908): (DnaJ heat shock protein family (Hsp40) member C12) This gene encodes a member of a subclass of the HSP40/DnaJ protein family. Members of this family of proteins are associated with complex assembly, protein folding, and export. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

DNAJC12 Gene-Disease associations (from GenCC):

• hyperphenylalaninemia due to DNAJC12 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

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_021800.3. 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
	DNAJC12	NM_021800.3	MANE Select	c.533G>C	p.Arg178Pro	missense	Exon 5 of 5	NP_068572.1	Q9UKB3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC12	ENST00000225171.7	TSL:1 MANE Select	c.533G>C	p.Arg178Pro	missense	Exon 5 of 5	ENSP00000225171.2	Q9UKB3-1
	DNAJC12	ENST00000483798.6	TSL:3	c.623G>C	p.Arg208Pro	missense	Exon 6 of 6	ENSP00000474215.1	S4R3E2
	DNAJC12	ENST00000857833.1		c.314G>C	p.Arg105Pro	missense	Exon 3 of 3	ENSP00000527892.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461378 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726946

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

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111748

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.094	T
Eigen	Benign	0.073
Eigen_PC	Benign	0.010
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		1.1
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.19
Sift	Benign	0.070	T
Sift4G	Benign	0.080	T
Polyphen		0.93	P
Vest4		0.65
MutPred		0.46		Loss of MoRF binding (P = 0.0028)
MVP		0.42
MPC		0.37
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.64
gMVP		0.63
Mutation Taster		=51/49	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: rs764261610; hg19: chr10-69556938;