19-3491733-G-A

Position:

chr19-3491733-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001145165.2(DOHH):c.668C>T(p.Pro223Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000816 in 1,506,464 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

DOHH
NM_001145165.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:3U:1

Conservation

PhyloP100: 7.29

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOHH	NM_001145165.2 linkuse as main transcript	c.668C>T	p.Pro223Leu	missense_variant	5/5	ENST00000427575.6	NP_001138637.1
DOHH	NM_031304.5 linkuse as main transcript	c.668C>T	p.Pro223Leu	missense_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.668C>T	p.Pro223Leu	missense_variant	5/5	1	NM_001145165.2	ENSP00000398882.1	Q9BU89
DOHH	ENST00000672935.1 linkuse as main transcript	c.668C>T	p.Pro223Leu	missense_variant	5/5			ENSP00000500806.1	Q9BU89
DOHH	ENST00000673168.1 linkuse as main transcript	n.461C>T		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151842

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

99554

Hom.:

AF XY:

0.0000359

AC XY:

AN XY:

55722

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:

0.00

Gnomad NFE exome

AF:

0.0000561

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000878

AC:

119

AN:

1354622

Hom.:

Cov.:

AF XY:

0.0000749

AC XY:

AN XY:

667498

show subpopulations

Gnomad4 AFR exome

AF:

0.0000360

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000110

Gnomad4 OTH exome

AF:

0.0000179

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151842

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74172

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

DOHH related neurodevelopmental disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	research	Department of Genetics, CHU d'Angers	Sep 22, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Spanish Undiagnosed Rare Disease Program-IIER, Instituto de Salud Carlos III	Aug 17, 2022	- -

Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 01, 2023	The DOHH c.668C>T, p.(Pro223Leu) variant was identified in trans with a likely pathogenic variant in a patient with neurodevelopmental abnormalities (Ziegler et al 2022). Purified recombinant protein containing this variant was found to have an in-vitro enzymatic activity that was comparable to that of the wild-type protein (Ziegler et al 2022). The highest frequency of this allele in the Genome Aggregation Database is 0.000078 in the European (non-Finnish) population, with no homozygous individuals reported (version 2.1.1). Multiple lines of computational evidence are inconclusive as to whether or not this variant will impact the gene or gene product. Based on the available evidence, the c.668C>T, p.(Pro223Leu) variant is classified as a variant of uncertain significance for neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 30, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.33

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

4.0

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.9

REVEL

Benign

0.25

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.010

Polyphen

0.65

Vest4

0.51

MutPred

0.52

Gain of stability (P = 0.0053);

MVP

0.46

MPC

0.81

ClinPred

0.99

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.51

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