NM_001040192.3:c.442A>G

Variant names:

• chr21-33488952-T-C
• rs1223902034
• NM_001040192.3:c.442A>G

Variant summary

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

The NM_001040192.3(DNAJC28):​c.442A>G​(p.Thr148Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DNAJC28 NM_001040192.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.70
• Publications: 0 publications found

Genes affected

DNAJC28 (HGNC:1297): (DnaJ heat shock protein family (Hsp40) member C28) This gene encodes a member of the DnaJ heat shock protein family. The encoded protein, which contains a conserved N-terminal DnaJ domain, is thought to play a role in protein folding or act as a molecular chaperone protein. [provided by RefSeq, Oct 2016]

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=0.1618067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC28	NM_001040192.3	c.442A>G	p.Thr148Ala	missense_variant	Exon 2 of 2	ENST00000381947.4	NP_001035282.1
DNAJC28	NM_001320746.3	c.442A>G	p.Thr148Ala	missense_variant	Exon 2 of 2		NP_001307675.1
DNAJC28	NM_017833.5	c.442A>G	p.Thr148Ala	missense_variant	Exon 2 of 2		NP_060303.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC28	ENST00000381947.4	c.442A>G	p.Thr148Ala	missense_variant	Exon 2 of 2	1	NM_001040192.3	ENSP00000371373.3
DNAJC28	ENST00000314399.3	c.442A>G	p.Thr148Ala	missense_variant	Exon 2 of 2	1		ENSP00000320303.3
DNAJC28	ENST00000402202.1	c.442A>G	p.Thr148Ala	missense_variant	Exon 2 of 2	5		ENSP00000385777.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251150 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461576 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727076

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

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111990

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.442A>G (p.T148A) alteration is located in exon 2 (coding exon 1) of the DNAJC28 gene. This alteration results from a A to G substitution at nucleotide position 442, causing the threonine (T) at amino acid position 148 to be replaced by an alanine (A). 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	0.060
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0016	T;T;T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.095
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;N;N
PhyloP100		5.7
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.18	.;N;N;N
REVEL	Benign	0.072
Sift	Uncertain	0.011	.;D;D;D
Sift4G	Benign	0.10	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.11
MutPred		0.25		Loss of phosphorylation at T148 (P = 0.0424);Loss of phosphorylation at T148 (P = 0.0424);Loss of phosphorylation at T148 (P = 0.0424);Loss of phosphorylation at T148 (P = 0.0424);
MVP		0.35
MPC		0.032
ClinPred		0.23	T
GERP RS		5.2
Varity_R		0.14
gMVP		0.16
Mutation Taster		=80/20	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: rs1223902034; hg19: chr21-34861259;