5-134777621-G-A

Position:

• chr5-134777621-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001300860.2(DDX46):​c.661G>A​(p.Glu221Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: DDX46 NM_001300860.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.66

Genes affected

DDX46 (HGNC:18681): (DEAD-box helicase 46) This gene encodes a member of the DEAD box protein family. 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. The protein encoded by this gene is a component of the 17S U2 snRNP complex; it plays an important role in pre-mRNA splicing. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2014]

DDX46 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30072445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX46	NM_001300860.2	c.661G>A	p.Glu221Lys	missense_variant	6/23	ENST00000452510.7	NP_001287789.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX46	ENST00000452510.7	c.661G>A	p.Glu221Lys	missense_variant	6/23	1	NM_001300860.2	ENSP00000416534.2
DDX46	ENST00000507392.5	n.517G>A		non_coding_transcript_exon_variant	5/23	2		ENSP00000427290.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2024

The c.661G>A (p.E221K) alteration is located in exon 6 (coding exon 6) of the DDX46 gene. This alteration results from a G to A substitution at nucleotide position 661, causing the glutamic acid (E) at amino acid position 221 to be replaced by a lysine (K). 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	0.25
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;.;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.2	.;.;L
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.0	.;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0060	.;D;D
Sift4G	Uncertain	0.038	D;D;D
Polyphen		0.96	.;.;P
Vest4		0.40
MutPred		0.26		.;Gain of ubiquitination at E221 (P = 0.0031);Gain of ubiquitination at E221 (P = 0.0031);
MVP		0.64
MPC		1.1
ClinPred		0.74	D
GERP RS		5.8
Varity_R		0.36
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-134113311;