X-23000457-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_182699.4(DDX53):c.400A>G(p.Ile134Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000241 in 1,210,189 control chromosomes in the GnomAD database, including 1 homozygotes. There are 107 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.00024 (1 hom. 98 hem.)
• Consequence: DDX53 NM_182699.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.279

Genes affected

DDX53 (HGNC:20083): (DEAD-box helicase 53) This intronless gene encodes a protein which contains several domains found in members of the DEAD-box helicase protein family. Other members of this protein family participate in ATP-dependent RNA unwinding. [provided by RefSeq, Sep 2011]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0146482885).
• BP6: Variant X-23000457-A-G is Benign according to our data. Variant chrX-23000457-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2204382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX53	NM_182699.4	c.400A>G	p.Ile134Val	missense_variant	1/1	ENST00000327968.7
PTCHD1-AS	NR_073010.2	n.343+63581T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX53	ENST00000327968.7	c.400A>G	p.Ile134Val	missense_variant	1/1		NM_182699.4	P1
	ENST00000687248.1	n.343+63581T>C		intron_variant, non_coding_transcript_variant
	ENST00000687119.1	n.83-56309T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000277 AC: 31 AN: 112025 Hom.: 0 Cov.: 23 AF XY: 0.000263 AC XY: 9 AN XY: 34189

Gnomad AFR AF: 0.0000650

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000472

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.000373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000357

Gnomad OTH AF: 0.00132

GnomAD3 exomes AF: 0.000354 AC: 65 AN: 183391 Hom.: 1 AF XY: 0.000442 AC XY: 30 AN XY: 67835

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000584

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000525

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000238 AC: 261 AN: 1098108 Hom.: 1 Cov.: 32 AF XY: 0.000270 AC XY: 98 AN XY: 363468

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.000767

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.000296

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000219

Gnomad4 OTH exome AF: 0.000434

GnomAD4 genome AF: 0.000277 AC: 31 AN: 112081 Hom.: 0 Cov.: 23 AF XY: 0.000263 AC XY: 9 AN XY: 34255

Gnomad4 AFR AF: 0.0000648

Gnomad4 AMR AF: 0.000471

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000281

Gnomad4 SAS AF: 0.000374

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000357

Gnomad4 OTH AF: 0.00130

Alfa AF: 0.00104 Hom.: 23

Bravo AF: 0.000295

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000764

EpiControl AF: 0.000771

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

DDX53-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 19, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

DDX53: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	0.050
Dann	Benign	0.53
DEOGEN2	Benign	0.0038	T
FATHMM_MKL	Benign	0.00036	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.0090
Sift	Benign	0.68	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.0040
MVP		0.043
MPC		0.075
ClinPred		0.0091	T
GERP RS		-2.3
Varity_R		0.026
gMVP		0.10

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: rs149084464; hg19: chrX-23018574;