rs1035794099

Positions:

• chr10-67811606-C-G
• chr10-67811606-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The ENST00000225171.7(DNAJC12):​c.215G>C​(p.Arg72Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAJC12 ENST00000225171.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.92

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 10-67811606-C-G is Pathogenic according to our data. Variant chr10-67811606-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 393302.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-67811606-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC12	NM_021800.3	c.215G>C	p.Arg72Pro	missense_variant	3/5	ENST00000225171.7	NP_068572.1
DNAJC12	NM_201262.2	c.215G>C	p.Arg72Pro	missense_variant	3/3		NP_957714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJC12	ENST00000225171.7	c.215G>C	p.Arg72Pro	missense_variant	3/5	1	NM_021800.3	ENSP00000225171	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyperphenylalaninemia due to DNAJC12 deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	4.2	H;.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.9	D;.;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.98
MutPred		0.87		Loss of MoRF binding (P = 6e-04);.;Loss of MoRF binding (P = 6e-04);
MVP		0.75
MPC		0.47
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.95
gMVP		0.88

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: rs1035794099; hg19: chr10-69571364; COSMIC: COSV56550162; COSMIC: COSV56550162;