chr19-3491746-C-CGGTT

Position:

chr19-3491746-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]

DOHH links:

DOHH (HGNC:):

DOHH links:

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
DOHH	NM_001145165.2 linkuse as main transcript	c.654_655insAACC	p.Glu219fs	frameshift_variant	5/5	ENST00000427575.6	NP_001138637.1
DOHH	NM_031304.5 linkuse as main transcript	c.654_655insAACC	p.Glu219fs	frameshift_variant	5/5		NP_112594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DOHH	ENST00000427575.6 linkuse as main transcript	c.654_655insAACC	p.Glu219fs	frameshift_variant	5/5	1	NM_001145165.2	ENSP00000398882.1	Q9BU89
DOHH	ENST00000672935.1 linkuse as main transcript	c.654_655insAACC	p.Glu219fs	frameshift_variant	5/5			ENSP00000500806.1	Q9BU89
DOHH	ENST00000673168.1 linkuse as main transcript	n.447_448insAACC		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes

AF:

0.000704

AC:

107

AN:

151972

Hom.:

Cov.:

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:

AN:

104072

Hom.:

AF XY:

0.000347

AC XY:

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.:

Cov.:

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.:

Cov.:

AF XY:

0.000659

AC XY:

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.:

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 submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	May 12, 2023	PVS1 PS3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 30, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 01, 2023	The 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 provided

research

Department of Genetics, CHU d'Angers

Sep 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.

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