X-23000376-G-T

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.319G>T(p.Ala107Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00401 in 1,206,710 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,522 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 0.0022 (0 hom., 63 hem., cov: 23)
  • Exomes 𝑓: 0.0042 (10 hom. 1459 hem.)
• Consequence: DDX53 NM_182699.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.345

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=0.004759252).
• BP6: Variant X-23000376-G-T is Benign according to our data. Variant chrX-23000376-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 716722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-23000376-G-T is described in Lovd as [Benign]. Variant chrX-23000376-G-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 63 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX53	NM_182699.4	c.319G>T	p.Ala107Ser	missense_variant	1/1	ENST00000327968.7
PTCHD1-AS	NR_073010.2	n.343+63662C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX53	ENST00000327968.7	c.319G>T	p.Ala107Ser	missense_variant	1/1		NM_182699.4	P1
	ENST00000687248.1	n.343+63662C>A		intron_variant, non_coding_transcript_variant
	ENST00000687119.1	n.83-56228C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 243 AN: 112297 Hom.: 0 Cov.: 23 AF XY: 0.00183 AC XY: 63 AN XY: 34445

Gnomad AFR AF: 0.000649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000941

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000327

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00407

Gnomad OTH AF: 0.00131

GnomAD3 exomes AF: 0.00204 AC: 364 AN: 178527 Hom.: 0 AF XY: 0.00205 AC XY: 130 AN XY: 63475

Gnomad AFR exome AF: 0.000612

Gnomad AMR exome AF: 0.0000755

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000314

Gnomad NFE exome AF: 0.00421

Gnomad OTH exome AF: 0.00227

GnomAD4 exome AF: 0.00420 AC: 4593 AN: 1094357 Hom.: 10 Cov.: 32 AF XY: 0.00405 AC XY: 1459 AN XY: 360171

Gnomad4 AFR exome AF: 0.000611

Gnomad4 AMR exome AF: 0.000145

Gnomad4 ASJ exome AF: 0.000209

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000189

Gnomad4 FIN exome AF: 0.000445

Gnomad4 NFE exome AF: 0.00525

Gnomad4 OTH exome AF: 0.00283

GnomAD4 genome AF: 0.00216 AC: 243 AN: 112353 Hom.: 0 Cov.: 23 AF XY: 0.00183 AC XY: 63 AN XY: 34511

Gnomad4 AFR AF: 0.000648

Gnomad4 AMR AF: 0.0000940

Gnomad4 ASJ AF: 0.000377

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000327

Gnomad4 NFE AF: 0.00407

Gnomad4 OTH AF: 0.00129

Alfa AF: 0.00399 Hom.: 173

Bravo AF: 0.00210

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00519 AC: 15

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00401 AC: 27

ExAC AF: 0.00210 AC: 255

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

DDX53-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.78
Dann	Benign	0.48
DEOGEN2	Benign	0.0044	T
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.026
Sift	Benign	0.60	T
Sift4G	Benign	0.76	T
Polyphen		0.24	B
Vest4		0.060
MVP		0.18
MPC		0.12
ClinPred		0.00082	T
GERP RS		-1.0
Varity_R		0.094
gMVP		0.32

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: rs148588561; hg19: chrX-23018493;