16-4450543-C-T

Variant names:

• chr16-4450543-C-T
• rs2304634
• NM_005147.6:c.1339+46C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005147.6(DNAJA3):​c.1339+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.656 in 1,449,482 control chromosomes in the GnomAD database, including 317,121 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.58 (27085 hom., cov: 32)
  • Exomes 𝑓: 0.66 (290036 hom.)
• Consequence: DNAJA3 NM_005147.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.48
• Publications: 16 publications found

Genes affected

DNAJA3 (HGNC:11808): (DnaJ heat shock protein family (Hsp40) member A3) This gene encodes a member of the DNAJ/Hsp40 protein family. DNAJ/Hsp40 proteins stimulate the ATPase activity of Hsp70 chaperones and play critical roles in protein folding, degradation, and multimeric complex assembly. The encoded protein is localized to mitochondria and mediates several cellular processes including proliferation, survival and apoptotic signal transduction. The encoded protein also plays a critical role in tumor suppression through interactions with oncogenic proteins including ErbB2 and the p53 tumor suppressor protein. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2011]

DNAJA3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005147.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJA3	NM_005147.6	MANE Select	c.1339+46C>T		intron	N/A	NP_005138.3
	DNAJA3	NM_001135110.3		c.1339+46C>T		intron	N/A	NP_001128582.1
	DNAJA3	NM_001286516.2		c.880+46C>T		intron	N/A	NP_001273445.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJA3	ENST00000262375.11	TSL:1 MANE Select	c.1339+46C>T		intron	N/A	ENSP00000262375.4
	DNAJA3	ENST00000355296.8	TSL:1	c.1339+46C>T		intron	N/A	ENSP00000347445.4
	DNAJA3	ENST00000431375.6	TSL:2	c.880+46C>T		intron	N/A	ENSP00000393970.2

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87756 AN: 151908 Hom.: 27069 Cov.: 32

Gnomad AFR AF: 0.361

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.726

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.596

GnomAD2 exomes AF: 0.629 AC: 104242 AN: 165720 AF XY: 0.633

Gnomad AFR exome AF: 0.362

Gnomad AMR exome AF: 0.591

Gnomad ASJ exome AF: 0.603

Gnomad EAS exome AF: 0.620

Gnomad FIN exome AF: 0.736

Gnomad NFE exome AF: 0.692

Gnomad OTH exome AF: 0.636

GnomAD4 exome AF: 0.665 AC: 862515 AN: 1297456 Hom.: 290036 Cov.: 17 AF XY: 0.662 AC XY: 426291 AN XY: 643710

African (AFR) AF: 0.353 AC: 10553 AN: 29934

American (AMR) AF: 0.575 AC: 20037 AN: 34840

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 14476 AN: 24020

East Asian (EAS) AF: 0.651 AC: 23277 AN: 35774

South Asian (SAS) AF: 0.538 AC: 40763 AN: 75700

European-Finnish (FIN) AF: 0.722 AC: 35787 AN: 49580

Middle Eastern (MID) AF: 0.567 AC: 3097 AN: 5460

European-Non Finnish (NFE) AF: 0.689 AC: 680276 AN: 987670

Other (OTH) AF: 0.629 AC: 34249 AN: 54478

GnomAD4 genome AF: 0.578 AC: 87812 AN: 152026 Hom.: 27085 Cov.: 32 AF XY: 0.576 AC XY: 42822 AN XY: 74286

African (AFR) AF: 0.362 AC: 15000 AN: 41472

American (AMR) AF: 0.559 AC: 8524 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 2066 AN: 3472

East Asian (EAS) AF: 0.632 AC: 3261 AN: 5156

South Asian (SAS) AF: 0.521 AC: 2512 AN: 4818

European-Finnish (FIN) AF: 0.726 AC: 7692 AN: 10594

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.691 AC: 46972 AN: 67952

Other (OTH) AF: 0.590 AC: 1242 AN: 2104

Alfa AF: 0.623 Hom.: 14186

Bravo AF: 0.557

Asia WGS AF: 0.488 AC: 1700 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.14
DANN	Benign	0.81
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs2304634; hg19: chr16-4500544; COSMIC: COSV52163025; COSMIC: COSV52163025;