16-72112468-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_014003.4(DHX38):ā€‹c.3655C>Gā€‹(p.Arg1219Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000048 in 1,459,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1219C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000048 ( 0 hom. )

Consequence

DHX38
NM_014003.4 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.54
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.37389994).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DHX38NM_014003.4 linkuse as main transcriptc.3655C>G p.Arg1219Gly missense_variant 27/27 ENST00000268482.8
DHX38XM_011523484.3 linkuse as main transcriptc.3655C>G p.Arg1219Gly missense_variant 27/28
DHX38XM_047434985.1 linkuse as main transcriptc.3655C>G p.Arg1219Gly missense_variant 27/28
DHX38XM_017023913.3 linkuse as main transcriptc.3550C>G p.Arg1184Gly missense_variant 26/27

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DHX38ENST00000268482.8 linkuse as main transcriptc.3655C>G p.Arg1219Gly missense_variant 27/271 NM_014003.4 P1Q92620-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000802
AC:
2
AN:
249304
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134966
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000480
AC:
7
AN:
1459832
Hom.:
0
Cov.:
31
AF XY:
0.00000551
AC XY:
4
AN XY:
726344
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 20, 2022This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1219 of the DHX38 protein (p.Arg1219Gly). This variant is present in population databases (rs772203418, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with DHX38-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.46
BayesDel_addAF
Benign
-0.039
T
BayesDel_noAF
Benign
-0.11
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.29
T;T
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Pathogenic
0.97
D;D
M_CAP
Benign
0.0082
T
MetaRNN
Benign
0.37
T;T
MetaSVM
Benign
-1.2
T
MutationAssessor
Uncertain
2.0
M;.
MutationTaster
Benign
0.99
D;D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-3.6
D;.
REVEL
Benign
0.16
Sift
Benign
0.033
D;.
Sift4G
Uncertain
0.012
D;D
Polyphen
0.93
P;.
Vest4
0.51
MutPred
0.22
Loss of MoRF binding (P = 0.0304);.;
MVP
0.61
MPC
1.6
ClinPred
0.92
D
GERP RS
5.3
Varity_R
0.36
gMVP
0.54

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.

Other links and lift over

dbSNP: rs772203418; hg19: chr16-72146367; API