12-124948170-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_032656.4(DHX37):​c.3302G>T​(p.Arg1101Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1101C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Consequence

DHX37
NM_032656.4 missense

Scores

8
8
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.74
Variant links:
Genes affected
DHX37 (HGNC:17210): (DEAH-box helicase 37) This gene encodes a DEAD box protein. 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. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DHX37NM_032656.4 linkc.3302G>T p.Arg1101Leu missense_variant Exon 26 of 27 ENST00000308736.7 NP_116045.2 Q8IY37
DHX37XM_005253590.4 linkc.3302G>T p.Arg1101Leu missense_variant Exon 26 of 26 XP_005253647.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DHX37ENST00000308736.7 linkc.3302G>T p.Arg1101Leu missense_variant Exon 26 of 27 1 NM_032656.4 ENSP00000311135.2 Q8IY37
DHX37ENST00000544745.2 linkc.2771G>T p.Arg924Leu missense_variant Exon 23 of 23 1 ENSP00000439009.2 F5H3Y4
DHX37ENST00000507267.2 linkn.446G>T non_coding_transcript_exon_variant Exon 1 of 2 1
DHX37ENST00000542400.5 linkn.1916G>T non_coding_transcript_exon_variant Exon 5 of 6 2

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
34

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Sep 27, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1101 of the DHX37 protein (p.Arg1101Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DHX37-related conditions. 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: "Possibly Damaging"; 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.80
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.27
T;T
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;.
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.84
D;D
MetaSVM
Benign
-1.0
T
MutationAssessor
Pathogenic
3.2
M;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-6.5
D;D
REVEL
Uncertain
0.41
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
1.0
D;D
Vest4
0.90
MutPred
0.54
Loss of MoRF binding (P = 0.0084);.;
MVP
0.67
MPC
0.66
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.73
gMVP
0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-125432716; API