Genetic Variant NM_182699.4:c.80G>T (chrX-23000137-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_182699.4(DDX53):c.80G>T(p.Ser27Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000926 in 1,079,856 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S27N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 9.3e-7 ( 0 hom. 0 hem. )

Consequence

DDX53
NM_182699.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.598

Publications

0 publications found

Variant links:

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]

DDX53 links:

PTCHD1-AS (HGNC:37703): (PTCHD1 antisense RNA (head to head))

PTCHD1-AS links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08281636).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX53	NM_182699.4 link	c.80G>T	p.Ser27Ile	missense_variant	Exon 1 of 1	ENST00000327968.7	NP_874358.2	Q86TM3
PTCHD1-AS	NR_073010.2 link	n.343+63901C>A		intron_variant	Intron 3 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DDX53	ENST00000327968.7 link	c.80G>T	p.Ser27Ile	missense_variant	Exon 1 of 1	6	NM_182699.4	ENSP00000368667.2	Q86TM3
PTCHD1-AS	ENST00000687119.1 link	n.83-55989C>A		intron_variant	Intron 1 of 3
PTCHD1-AS	ENST00000687248.2 link	n.371+63901C>A		intron_variant	Intron 3 of 8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.26e-7

AC:

AN:

1079856

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

349900

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25814

American (AMR)

AF:

0.00

AC:

AN:

33057

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18517

East Asian (EAS)

AF:

0.00

AC:

AN:

29872

South Asian (SAS)

AF:

0.00

AC:

AN:

50716

European-Finnish (FIN)

AF:

0.0000249

AC:

AN:

40165

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3915

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

832648

Other (OTH)

AF:

0.00

AC:

AN:

45152

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.013

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.24

M_CAP

Benign

0.011

MetaRNN

Benign

0.083

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

0.60

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.050

Sift

Benign

0.052

Sift4G

Benign

0.19

Polyphen

0.20

Vest4

0.094

MutPred

0.23

Loss of disorder (P = 0.0049);

MVP

0.043

MPC

0.12

ClinPred

0.11

GERP RS

3.0

PromoterAI

-0.027

Neutral

(source)

Varity_R

0.14

gMVP

0.39

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over