chr19-3492327-C-G

Position:

• chr19-3492327-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001145165.2(DOHH):​c.524G>C​(p.Arg175Pro) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DOHH NM_001145165.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOHH	NM_001145165.2	c.524G>C	p.Arg175Pro	missense_variant	4/5	ENST00000427575.6	NP_001138637.1
DOHH	NM_031304.5	c.524G>C	p.Arg175Pro	missense_variant	4/5		NP_112594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOHH	ENST00000427575.6	c.524G>C	p.Arg175Pro	missense_variant	4/5	1	NM_001145165.2	ENSP00000398882.1
DOHH	ENST00000672935.1	c.524G>C	p.Arg175Pro	missense_variant	4/5			ENSP00000500806.1
DOHH	ENST00000671696.1	c.377G>C	p.Arg126Pro	missense_variant	3/3			ENSP00000499813.1
DOHH	ENST00000673168.1	n.317G>C		non_coding_transcript_exon_variant	2/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000702 AC: 1 AN: 142406 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 79566

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000393

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 23, 2024

Variant summary: DOHH c.524G>C (p.Arg175Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7e-06 in 142406 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.524G>C in individuals affected with Neurodevelopmental Disorder With Microcephaly, Cerebral Atrophy, And Visual Impairment and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.068	D
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.027	D
Polyphen		0.67	P
Vest4		0.96
MutPred		0.76		Loss of MoRF binding (P = 0.0274);
MVP		0.53
MPC		1.0
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.98
gMVP		0.90

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

Other links and lift over

dbSNP: rs1314195440; hg19: chr19-3492325;