16-70333558-C-A

Variant names:

• chr16-70333558-C-A
• rs74026003
• NM_007242.7:c.1416C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007242.7(DDX19B):​c.1416C>A​(p.Asp472Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DDX19B NM_007242.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.256

Genes affected

DDX19B (HGNC:2742): (DEAD-box helicase 19B) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which exhibits RNA-dependent ATPase and ATP-dependent RNA-unwinding activities. This protein is recruited to the cytoplasmic fibrils of the nuclear pore complex, where it participates in the export of mRNA from the nucleus. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ENSG00000260537 (HGNC:):

DDX19A-DT (HGNC:55349): (DDX19A divergent transcript)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08190289).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX19B	NM_007242.7	c.1416C>A	p.Asp472Glu	missense_variant	Exon 12 of 12	ENST00000288071.11	NP_009173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX19B	ENST00000288071.11	c.1416C>A	p.Asp472Glu	missense_variant	Exon 12 of 12	1	NM_007242.7	ENSP00000288071.7
ENSG00000260537	ENST00000443119.7	c.160+18603C>A		intron_variant	Intron 3 of 11	5		ENSP00000399208.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251154 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461672 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1416C>A (p.D472E) alteration is located in exon 12 (coding exon 12) of the DDX19B gene. This alteration results from a C to A substitution at nucleotide position 1416, causing the aspartic acid (D) at amino acid position 472 to be replaced by a glutamic acid (E). 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	Pathogenic	0.64
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.13
DANN	Benign	0.96
DEOGEN2	Benign	0.072	.;T;.;.;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.50	N
LIST_S2	Uncertain	0.95	.;D;D;.;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.082	T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.55	.;.;.;.;N;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D;D
REVEL	Benign	0.23
Sift	Benign	0.14	T;T;T;T;T;T;T
Sift4G	Benign	0.33	T;T;T;T;T;T;T
Polyphen		0.0060, 0.039	.;.;.;.;B;.;B
Vest4		0.38
MutPred		0.37		.;.;.;.;Loss of ubiquitination at K476 (P = 0.1139);.;.;
MVP		0.16
MPC		1.5
ClinPred		0.13	T
GERP RS		-8.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.93

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: rs74026003; hg19: chr16-70367461;