chr19-3492310-C-A

Position:

• chr19-3492310-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001145165.2(DOHH):​c.541G>T​(p.Ala181Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000722 in 1,384,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DOHH NM_001145165.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.73

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29961443).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOHH	NM_001145165.2	c.541G>T	p.Ala181Ser	missense_variant	4/5	ENST00000427575.6	NP_001138637.1
DOHH	NM_031304.5	c.541G>T	p.Ala181Ser	missense_variant	4/5		NP_112594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOHH	ENST00000427575.6	c.541G>T	p.Ala181Ser	missense_variant	4/5	1	NM_001145165.2	ENSP00000398882.1
DOHH	ENST00000672935.1	c.541G>T	p.Ala181Ser	missense_variant	4/5			ENSP00000500806.1
DOHH	ENST00000671696.1	c.394G>T	p.Ala132Ser	missense_variant	3/3			ENSP00000499813.1
DOHH	ENST00000673168.1	n.334G>T		non_coding_transcript_exon_variant	2/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1384586 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 685270

Gnomad4 AFR exome AF: 0.00

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: 9.24e-7

Gnomad4 OTH exome AF: 0.00

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

Ambry Genetics

Apr 11, 2023

The c.541G>T (p.A181S) alteration is located in exon 4 (coding exon 3) of the DOHH gene. This alteration results from a G to T substitution at nucleotide position 541, causing the alanine (A) at amino acid position 181 to be replaced by a serine (S). 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	0.091
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.064
Eigen_PC	Benign	0.0091
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.5	L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.080	N
REVEL	Benign	0.17
Sift	Benign	0.47	T
Sift4G	Benign	0.54	T
Polyphen		0.41	B
Vest4		0.52
MutPred		0.33		Gain of disorder (P = 0.066);
MVP		0.28
MPC		0.50
ClinPred		0.66	D
GERP RS		4.3
Varity_R		0.25
gMVP		0.26

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: rs755986071; hg19: chr19-3492308;