Genetic Variant DDX46:p.Thr260Met (chr5-134781146-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001300860.2(DDX46):c.779C>T(p.Thr260Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,578,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

DDX46
NM_001300860.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.93

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07255021).

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX46	NM_001300860.2 link	c.779C>T	p.Thr260Met	missense_variant	Exon 7 of 23	ENST00000452510.7	NP_001287789.1	Q7L014A0A0C4DG89

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX46	ENST00000452510.7 link	c.779C>T	p.Thr260Met	missense_variant	Exon 7 of 23	1	NM_001300860.2	ENSP00000416534.2		A0A0C4DG89
DDX46	ENST00000507392.5 link	n.635C>T		non_coding_transcript_exon_variant	Exon 6 of 23	2		ENSP00000427290.1		D6RJA6

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000371

AC:

AN:

215630

Hom.:

AF XY:

0.0000511

AC XY:

AN XY:

117498

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000450

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000195

Gnomad SAS exome

AF:

0.000128

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000955

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000252

AC:

AN:

1426198

Hom.:

Cov.:

AF XY:

0.0000324

AC XY:

AN XY:

709420

show subpopulations

Gnomad4 AFR exome

AF:

0.0000653

Gnomad4 AMR exome

AF:

0.0000310

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000130

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000127

Gnomad4 OTH exome

AF:

0.0000509

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.779C>T (p.T260M) alteration is located in exon 7 (coding exon 7) of the DDX46 gene. This alteration results from a C to T substitution at nucleotide position 779, causing the threonine (T) at amino acid position 260 to be replaced by a methionine (M). 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

0.14

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.56

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.016

T;.;T

Eigen

Benign

-0.071

Eigen_PC

Benign

0.073

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.0079

MetaRNN

Benign

0.073

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

.;.;N

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.1

.;N;N

REVEL

Benign

0.11

Sift

Benign

0.042

.;D;D

Sift4G

Benign

0.11

T;T;T

Polyphen

0.096

.;.;B

Vest4

0.20

MutPred

0.22

.;Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);

MVP

0.26

MPC

0.92

ClinPred

0.048

GERP RS

5.0

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

0.11

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over