19-3491746-C-CGGTT

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_001145165.2(DOHH):​c.654_655insAACC​(p.Glu219fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,511,436 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0010 ( 0 hom. )

Consequence

DOHH
NM_001145165.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.304
Variant links:
Genes affected
DOHH (HGNC:28662): (deoxyhypusine hydroxylase) This gene encodes a metalloenzyme that catalyzes the last step in the conversion of lysine to the unique amino acid hypusine in eukaryotic initiation factor 5A. The encoded protein hydroxylates deoxyhypusine to form hypusine in the mature eukaryotic initiation factor 5A protein. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-3491746-C-CGGTT is Pathogenic according to our data. Variant chr19-3491746-C-CGGTT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1285602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DOHHNM_001145165.2 linkuse as main transcriptc.654_655insAACC p.Glu219fs frameshift_variant 5/5 ENST00000427575.6 NP_001138637.1
DOHHNM_031304.5 linkuse as main transcriptc.654_655insAACC p.Glu219fs frameshift_variant 5/5 NP_112594.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DOHHENST00000427575.6 linkuse as main transcriptc.654_655insAACC p.Glu219fs frameshift_variant 5/51 NM_001145165.2 ENSP00000398882.1 Q9BU89
DOHHENST00000672935.1 linkuse as main transcriptc.654_655insAACC p.Glu219fs frameshift_variant 5/5 ENSP00000500806.1 Q9BU89
DOHHENST00000673168.1 linkuse as main transcriptn.447_448insAACC non_coding_transcript_exon_variant 3/3

Frequencies

GnomAD3 genomes
AF:
0.000704
AC:
107
AN:
151972
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00134
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000327
AC:
34
AN:
104072
Hom.:
0
AF XY:
0.000347
AC XY:
20
AN XY:
57702
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:
0.00
Gnomad FIN exome
AF:
0.000296
Gnomad NFE exome
AF:
0.000793
Gnomad OTH exome
AF:
0.000324
GnomAD4 exome
AF:
0.00103
AC:
1405
AN:
1359346
Hom.:
0
Cov.:
32
AF XY:
0.00100
AC XY:
673
AN XY:
669876
show subpopulations
Gnomad4 AFR exome
AF:
0.0000358
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000435
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000991
Gnomad4 NFE exome
AF:
0.00125
Gnomad4 OTH exome
AF:
0.000445
GnomAD4 genome
AF:
0.000704
AC:
107
AN:
152090
Hom.:
0
Cov.:
32
AF XY:
0.000659
AC XY:
49
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000377
Gnomad4 NFE
AF:
0.00134
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000291
Hom.:
0
Bravo
AF:
0.000586

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterMay 12, 2023PVS1 PS3 -
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 30, 2022- -
Likely pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 01, 2023The DOHH c.654_655insAACC p.(Glu219AsnfsTer54) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected; however any truncated protein that is produced will lack the carboxy-terminal HEAT domains which are important for iron binding and enzyme activity (Kim et al 2006). This variant has been reported in trans with two different missense variants in patients from two unrelated families with neurodevelopmental abnormalities, one of whom was biochemically tested and found to have reduced DOHH protein level and enzyme activity (Ziegler et al 2022). In one of these families this variant segregated with disease in two siblings together with the other missense variant. Purified recombinant truncated protein resulting from this variant was found to have no enzymatic activity in-vitro (Ziegler et al 2022). The highest frequency of this allele in the Genome Aggregation Database is 0.001339 in the European (non-Finnish) population, with no homozygous individuals reported (version 3.1.2). Based on the available evidence, the c.654_655insAACC p.(Glu219AsnfsTer54) variant is classified as likely pathogenic for neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment. -
DOHH related neurodevelopmental disorder Pathogenic:1
Pathogenic, no assertion criteria providedresearchDepartment of Genetics, CHU d'AngersSep 22, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs761870531; hg19: chr19-3491744; API