Variant 19-3491739-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001145165.2(DOHH):c.662C>T(p.Ala221Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,510,140 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 (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

DOHH
NM_001145165.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.41

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03848988).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOHH	NM_001145165.2 link	c.662C>T	p.Ala221Val	missense_variant	5/5	ENST00000427575.6	NP_001138637.1
DOHH	NM_031304.5 link	c.662C>T	p.Ala221Val	missense_variant	5/5		NP_112594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DOHH	ENST00000427575.6 link	c.662C>T	p.Ala221Val	missense_variant	5/5	1	NM_001145165.2	ENSP00000398882.1	Q9BU89
DOHH	ENST00000672935.1 link	c.662C>T	p.Ala221Val	missense_variant	5/5			ENSP00000500806.1	Q9BU89
DOHH	ENST00000673168.1 link	n.455C>T		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1358194

Hom.:

Cov.:

AF XY:

0.0000149

AC XY:

AN XY:

669260

show subpopulations

Gnomad4 AFR exome

AF:

0.000143

Gnomad4 AMR exome

AF:

0.000110

Gnomad4 ASJ exome

AF:

0.0000436

Gnomad4 EAS exome

AF:

0.0000591

Gnomad4 SAS exome

AF:

0.0000268

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.39e-7

Gnomad4 OTH exome

AF:

0.0000356

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151946

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74214

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.000280

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000277

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2024

The c.662C>T (p.A221V) alteration is located in exon 5 (coding exon 4) of the DOHH gene. This alteration results from a C to T substitution at nucleotide position 662, causing the alanine (A) at amino acid position 221 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

Eigen

Benign

0.014

Eigen_PC

Benign

-0.086

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.038

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.14

Sift

Benign

0.047

Sift4G

Uncertain

0.043

Polyphen

0.54

Vest4

0.24

MVP

0.41

MPC

0.49

ClinPred

0.12

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.34

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