5-134796012-T-C

Variant names:

• chr5-134796012-T-C
• rs755327824
• NM_001300860.2:c.1816T>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001300860.2(DDX46):​c.1816T>C​(p.Phe606Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000274 in 1,613,180 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: DDX46 NM_001300860.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.95

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX46	NM_001300860.2	c.1816T>C	p.Phe606Leu	missense_variant	Exon 15 of 23	ENST00000452510.7	NP_001287789.1
DDX46	NM_014829.4	c.1816T>C	p.Phe606Leu	missense_variant	Exon 15 of 23		NP_055644.2
DDX46	NR_125341.2	n.1949T>C		non_coding_transcript_exon_variant	Exon 15 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX46	ENST00000452510.7	c.1816T>C	p.Phe606Leu	missense_variant	Exon 15 of 23	1	NM_001300860.2	ENSP00000416534.2
DDX46	ENST00000507392.5	n.*373T>C		non_coding_transcript_exon_variant	Exon 15 of 23	2		ENSP00000427290.1
DDX46	ENST00000507392.5	n.*373T>C		3_prime_UTR_variant	Exon 15 of 23	2		ENSP00000427290.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000156 AC: 39 AN: 250388 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135358

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000285 AC: 417 AN: 1460952 Hom.: 0 Cov.: 30 AF XY: 0.000256 AC XY: 186 AN XY: 726814

Gnomad4 AFR exome AF: 0.0000598

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: 0.00103

Gnomad4 NFE exome AF: 0.000312

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74382

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000300 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1816T>C (p.F606L) alteration is located in exon 15 (coding exon 15) of the DDX46 gene. This alteration results from a T to C substitution at nucleotide position 1816, causing the phenylalanine (F) at amino acid position 606 to be replaced by a leucine (L). 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	0.95
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	.;D
Eigen	Benign	0.043
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.020	D
MutationAssessor	Benign	-0.085	.;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Uncertain	0.59
Sift	Benign	0.031	D;D
Sift4G	Uncertain	0.056	T;T
Polyphen		0.19	.;B
Vest4		0.71
MutPred		0.28		Loss of methylation at K605 (P = 0.03);Loss of methylation at K605 (P = 0.03);
MVP		0.95
MPC		1.8
ClinPred		0.11	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.88

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: rs755327824; hg19: chr5-134131702;