16-72112475-C-T

Position:

chr16-72112475-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_014003.4(DHX38):c.3662C>T(p.Thr1221Met) variant causes a missense change. The variant allele was found at a frequency of 0.00155 in 1,612,246 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1221T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 6 hom. )

Consequence

DHX38
NM_014003.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.07

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:

PMFBP1 (HGNC:17728): (polyamine modulated factor 1 binding protein 1) Involved in spermatogenesis. Located in sperm connecting piece. Implicated in spermatogenic failure 31. [provided by Alliance of Genome Resources, Apr 2022]

PMFBP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.036486864).

BP6

Variant 16-72112475-C-T is Benign according to our data. Variant chr16-72112475-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 733154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DHX38	NM_014003.4 linkuse as main transcript	c.3662C>T	p.Thr1221Met	missense_variant	27/27	ENST00000268482.8
DHX38	XM_011523484.3 linkuse as main transcript	c.3662C>T	p.Thr1221Met	missense_variant	27/28
DHX38	XM_047434985.1 linkuse as main transcript	c.3662C>T	p.Thr1221Met	missense_variant	27/28
DHX38	XM_017023913.3 linkuse as main transcript	c.3557C>T	p.Thr1186Met	missense_variant	26/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHX38	ENST00000268482.8 linkuse as main transcript	c.3662C>T	p.Thr1221Met	missense_variant	27/27	1	NM_014003.4	P1	Q92620-1

Frequencies

GnomAD3 genomes

AF:

0.00107

AC:

163

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00193

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00119

AC:

296

AN:

249434

Hom.:

AF XY:

0.00124

AC XY:

168

AN XY:

135034

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00187

Gnomad NFE exome

AF:

0.00194

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00160

AC:

2330

AN:

1459904

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

1131

AN XY:

726388

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000715

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00150

Gnomad4 NFE exome

AF:

0.00192

Gnomad4 OTH exome

AF:

0.00109

GnomAD4 genome

AF:

0.00107

AC:

163

AN:

152342

Hom.:

Cov.:

AF XY:

0.000980

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00193

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00153

Hom.:

Bravo

AF:

0.000876

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00125

AC:

152

EpiCase

AF:

0.00196

EpiControl

AF:

0.00178

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	DHX38: BS2 -

DHX38-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 28, 2020

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

Uncertain

0.34

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

T;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.6

D;.

REVEL

Benign

0.22

Sift

Uncertain

0.0020

D;.

Sift4G

Uncertain

0.051

T;D

Polyphen

1.0

D;.

Vest4

0.72

MVP

0.66

MPC

1.5

ClinPred

0.20

GERP RS

5.3

Varity_R

0.28

gMVP

0.46

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