10-67797210-C-T

Variant names:

• chr10-67797210-C-T
• rs781133305
• NM_021800.3:c.503G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021800.3(DNAJC12):​c.503G>A​(p.Gly168Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G168V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNAJC12 NM_021800.3 missense, splice_region
• Scores: Splicing: ADA: 0.0007436
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.454
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.077500254).

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.503G>A	p.Gly168Asp	missense splice_region	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.503G>A	p.Gly168Asp	missense splice_region	Exon 5 of 5	ENSP00000225171.2	Q9UKB3-1
	DNAJC12	ENST00000483798.6	TSL:3	c.593G>A	p.Gly198Asp	missense splice_region	Exon 6 of 6	ENSP00000474215.1	S4R3E2
	DNAJC12	ENST00000857833.1		c.284G>A	p.Gly95Asp	missense splice_region	Exon 3 of 3	ENSP00000527892.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459906 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726194

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 85912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110944

Other (OTH) AF: 0.00 AC: 0 AN: 60326

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	13
DANN	Benign	0.85
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.45
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.031
Sift	Benign	0.19	T
Sift4G	Benign	0.21	T
Polyphen		0.047	B
Vest4		0.068
MutPred		0.41		Loss of glycosylation at S167 (P = 0.0555)
MVP		0.14
MPC		0.093
ClinPred		0.050	T
GERP RS		-0.57
Varity_R		0.069
gMVP		0.077
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00074
dbscSNV1_RF	Benign	0.098
SpliceAI score (max)		0.050		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: rs781133305; hg19: chr10-69556968;