5-55786646-C-T

Variant names:

• chr5-55786646-C-T
• rs957459
• NM_024415.3:c.993C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_024415.3(DDX4):​c.993C>T​(p.Cys331Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 1,610,654 control chromosomes in the GnomAD database, including 97,204 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 0.40 (13953 hom., cov: 32)
  • Exomes 𝑓: 0.33 (83251 hom.)
• Consequence: DDX4 NM_024415.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86
• Publications: 12 publications found

Genes affected

DDX4 (HGNC:18700): (DEAD-box helicase 4) 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 is a homolog of VASA proteins in Drosophila and several other species. The gene is specifically expressed in the germ cell lineage in both sexes and functions in germ cell development. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP7: Synonymous conserved (PhyloP=1.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX4	NM_024415.3	c.993C>T	p.Cys331Cys	synonymous_variant	Exon 14 of 22	ENST00000505374.6	NP_077726.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX4	ENST00000505374.6	c.993C>T	p.Cys331Cys	synonymous_variant	Exon 14 of 22	1	NM_024415.3	ENSP00000424838.1

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61428 AN: 151808 Hom.: 13913 Cov.: 32

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.488

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.308

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.393

GnomAD2 exomes AF: 0.378 AC: 94927 AN: 251222 AF XY: 0.361

Gnomad AFR exome AF: 0.600

Gnomad AMR exome AF: 0.608

Gnomad ASJ exome AF: 0.325

Gnomad EAS exome AF: 0.482

Gnomad FIN exome AF: 0.266

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.360

GnomAD4 exome AF: 0.328 AC: 478387 AN: 1458728 Hom.: 83251 Cov.: 32 AF XY: 0.325 AC XY: 236059 AN XY: 725854

African (AFR) AF: 0.610 AC: 20386 AN: 33398

American (AMR) AF: 0.595 AC: 26621 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 8354 AN: 26110

East Asian (EAS) AF: 0.473 AC: 18750 AN: 39646

South Asian (SAS) AF: 0.305 AC: 26270 AN: 86148

European-Finnish (FIN) AF: 0.266 AC: 14190 AN: 53374

Middle Eastern (MID) AF: 0.339 AC: 1951 AN: 5760

European-Non Finnish (NFE) AF: 0.307 AC: 341061 AN: 1109314

Other (OTH) AF: 0.345 AC: 20804 AN: 60266

GnomAD4 genome AF: 0.405 AC: 61528 AN: 151926 Hom.: 13953 Cov.: 32 AF XY: 0.403 AC XY: 29975 AN XY: 74290

African (AFR) AF: 0.593 AC: 24555 AN: 41412

American (AMR) AF: 0.487 AC: 7436 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1179 AN: 3466

East Asian (EAS) AF: 0.475 AC: 2452 AN: 5164

South Asian (SAS) AF: 0.309 AC: 1490 AN: 4822

European-Finnish (FIN) AF: 0.254 AC: 2685 AN: 10558

Middle Eastern (MID) AF: 0.317 AC: 92 AN: 290

European-Non Finnish (NFE) AF: 0.302 AC: 20548 AN: 67938

Other (OTH) AF: 0.390 AC: 824 AN: 2112

Alfa AF: 0.342 Hom.: 19036

Bravo AF: 0.438

Asia WGS AF: 0.410 AC: 1427 AN: 3478

EpiCase AF: 0.306

EpiControl AF: 0.309

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	13
DANN	Benign	0.68
PhyloP100		1.9
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: rs957459; hg19: chr5-55082474; COSMIC: COSV61754181; COSMIC: COSV61754181;