chr16-72112418-C-T

Position:

chr16-72112418-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014003.4(DHX38):c.3605C>T(p.Thr1202Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,608,820 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

DHX38
NM_014003.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.22

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:

DHX38 (HGNC:):

DHX38 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09889984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHX38	NM_014003.4 linkuse as main transcript	c.3605C>T	p.Thr1202Met	missense_variant	27/27	ENST00000268482.8	NP_054722.2	Q92620-1
DHX38	XM_011523484.3 linkuse as main transcript	c.3605C>T	p.Thr1202Met	missense_variant	27/28		XP_011521786.1	Q92620-1
DHX38	XM_047434985.1 linkuse as main transcript	c.3605C>T	p.Thr1202Met	missense_variant	27/28		XP_047290941.1
DHX38	XM_017023913.3 linkuse as main transcript	c.3500C>T	p.Thr1167Met	missense_variant	26/27		XP_016879402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHX38	ENST00000268482.8 linkuse as main transcript	c.3605C>T	p.Thr1202Met	missense_variant	27/27	1	NM_014003.4	ENSP00000268482.3		Q92620-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000203

AC:

AN:

246178

Hom.:

AF XY:

0.00000749

AC XY:

AN XY:

133436

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1456642

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

724890

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2022

The c.3605C>T (p.T1202M) alteration is located in exon 27 (coding exon 26) of the DHX38 gene. This alteration results from a C to T substitution at nucleotide position 3605, causing the threonine (T) at amino acid position 1202 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 25, 2022

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. 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"). ClinVar contains an entry for this variant (Variation ID: 1479683). This variant has not been reported in the literature in individuals affected with DHX38-related conditions. This variant is present in population databases (rs564071619, gnomAD 0.02%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1202 of the DHX38 protein (p.Thr1202Met). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.063

T;T

Eigen

Benign

-0.019

Eigen_PC

Benign

0.061

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.099

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.70

N;.

REVEL

Benign

0.064

Sift

Benign

0.11

T;.

Sift4G

Benign

0.12

T;T

Polyphen

0.79

P;.

Vest4

0.11

MutPred

0.48

Loss of phosphorylation at T1202 (P = 0.0013);.;

MVP

0.50

MPC

0.61

ClinPred

0.12

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.024

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