16-72096212-G-A

Position:

chr16-72096212-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000268482.8(DHX38):c.55G>A(p.Asp19Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,614,064 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00088 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 2 hom. )

Consequence

DHX38
ENST00000268482.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.64

Variant links:

Genes affected

DHX38 (HGNC:17211): (DEAH-box helicase 38) 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 member of the DEAD/H box family of splicing factors. This protein resembles yeast Prp16 more closely than other DEAD/H family members. It is an ATPase and essential for the catalytic step II in pre-mRNA splicing process. [provided by RefSeq, Jul 2008]

DHX38 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009580553).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHX38	NM_014003.4 linkuse as main transcript	c.55G>A	p.Asp19Asn	missense_variant	2/27	ENST00000268482.8	NP_054722.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHX38	ENST00000268482.8 linkuse as main transcript	c.55G>A	p.Asp19Asn	missense_variant	2/27	1	NM_014003.4	ENSP00000268482	P1	Q92620-1
DHX38	ENST00000566794.5 linkuse as main transcript	c.55G>A	p.Asp19Asn	missense_variant	2/3	4		ENSP00000455939
DHX38	ENST00000566489.1 linkuse as main transcript	c.55G>A	p.Asp19Asn	missense_variant	3/4	4		ENSP00000457887
DHX38	ENST00000579387.5 linkuse as main transcript	c.55G>A	p.Asp19Asn	missense_variant, NMD_transcript_variant	2/12	5		ENSP00000462149

Frequencies

GnomAD3 genomes

AF:

0.000880

AC:

134

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00160

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000777

AC:

195

AN:

250882

Hom.:

AF XY:

0.000766

AC XY:

104

AN XY:

135708

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00155

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.00150

AC:

2190

AN:

1461746

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

1061

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000750

Gnomad4 NFE exome

AF:

0.00185

Gnomad4 OTH exome

AF:

0.00166

GnomAD4 genome

AF:

0.000880

AC:

134

AN:

152318

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00160

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00127

Hom.:

Bravo

AF:

0.000948

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000865

AC:

105

EpiCase

AF:

0.00180

EpiControl

AF:

0.00142

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 84

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 03, 2022

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 19 of the DHX38 protein (p.Asp19Asn). This variant is present in population databases (rs145829337, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DHX38-related conditions. ClinVar contains an entry for this variant (Variation ID: 858580). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.048

T;.;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.81

T;T;T

M_CAP

Benign

0.0039

MetaRNN

Benign

0.0096

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

N;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.10

N;N;N

REVEL

Benign

0.044

Sift

Benign

0.74

T;T;T

Sift4G

Benign

0.49

T;T;T

Polyphen

0.012

B;.;.

Vest4

0.091

MVP

0.35

MPC

0.19

ClinPred

0.0043

GERP RS

4.7

Varity_R

0.040

gMVP

0.13

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

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