rs1051519

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005327.7(HADH):​c.456G>T​(p.Gln152His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,613,826 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0026 ( 3 hom. )

Consequence

HADH
NM_005327.7 missense

Scores

5
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:5

Conservation

PhyloP100: 1.35
Variant links:
Genes affected
HADH (HGNC:4799): (hydroxyacyl-CoA dehydrogenase) This gene is a member of the 3-hydroxyacyl-CoA dehydrogenase gene family. The encoded protein functions in the mitochondrial matrix to catalyze the oxidation of straight-chain 3-hydroxyacyl-CoAs as part of the beta-oxidation pathway. Its enzymatic activity is highest with medium-chain-length fatty acids. Mutations in this gene cause one form of familial hyperinsulinemic hypoglycemia. The human genome contains a related pseudogene of this gene on chromosome 15. [provided by RefSeq, May 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.02197808).
BP6
Variant 4-108019576-G-T is Benign according to our data. Variant chr4-108019576-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211127.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=1, Likely_benign=3}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00186 (284/152282) while in subpopulation NFE AF= 0.00378 (257/68028). AF 95% confidence interval is 0.0034. There are 0 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HADHNM_005327.7 linkc.456G>T p.Gln152His missense_variant Exon 4 of 8 ENST00000309522.8 NP_005318.6 Q16836-1A0A140VK76
HADHNM_001184705.4 linkc.456G>T p.Gln152His missense_variant Exon 4 of 9 NP_001171634.3 Q16836-3
HADHNM_001331027.2 linkc.468G>T p.Gln156His missense_variant Exon 4 of 8 NP_001317956.2 B3KTT6
HADHXR_007096395.1 linkn.500G>T non_coding_transcript_exon_variant Exon 4 of 8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HADHENST00000309522.8 linkc.456G>T p.Gln152His missense_variant Exon 4 of 8 1 NM_005327.7 ENSP00000312288.4 Q16836-1

Frequencies

GnomAD3 genomes
AF:
0.00187
AC:
284
AN:
152164
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00378
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.00180
AC:
452
AN:
251480
Hom.:
0
AF XY:
0.00175
AC XY:
238
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.000431
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000924
Gnomad NFE exome
AF:
0.00379
Gnomad OTH exome
AF:
0.00130
GnomAD4 exome
AF:
0.00259
AC:
3788
AN:
1461544
Hom.:
3
Cov.:
31
AF XY:
0.00249
AC XY:
1807
AN XY:
727074
show subpopulations
Gnomad4 AFR exome
AF:
0.000478
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.000337
Gnomad4 NFE exome
AF:
0.00329
Gnomad4 OTH exome
AF:
0.00152
GnomAD4 genome
AF:
0.00186
AC:
284
AN:
152282
Hom.:
0
Cov.:
32
AF XY:
0.00167
AC XY:
124
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.000481
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.00378
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00333
Hom.:
0
Bravo
AF:
0.00187
TwinsUK
AF:
0.00351
AC:
13
ALSPAC
AF:
0.00363
AC:
14
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00419
AC:
36
ExAC
AF:
0.00203
AC:
246
EpiCase
AF:
0.00322
EpiControl
AF:
0.00326

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3
Apr 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

HADH: BP4, BS1 -

Sep 12, 2022
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 20, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 8687463) -

Deficiency of 3-hydroxyacyl-CoA dehydrogenase Uncertain:1Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1
Jul 23, 2015
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Deficiency of 3-hydroxyacyl-CoA dehydrogenase;C1864948:Hyperinsulinemic hypoglycemia, familial, 4 Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Monogenic diabetes Uncertain:1
Mar 24, 2017
Personalized Diabetes Medicine Program, University of Maryland School of Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

ACMG Criteria:PP3 (3 predictors), BP4 (7 predictors) -

Hyperinsulinemic hypoglycemia, familial, 4 Uncertain:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

HADH-related disorder Benign:1
Dec 01, 2023
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
.;.;T;.;.
Eigen
Benign
-0.034
Eigen_PC
Benign
-0.0078
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.90
D;D;D;D;D
M_CAP
Benign
0.029
D
MetaRNN
Benign
0.022
T;T;T;T;T
MetaSVM
Benign
-0.78
T
MutationAssessor
Benign
1.6
.;L;L;.;.
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.8
.;.;N;N;.
REVEL
Uncertain
0.30
Sift
Benign
0.14
.;.;T;T;.
Sift4G
Benign
0.062
.;T;T;.;T
Polyphen
0.91
.;.;P;.;.
Vest4
0.36, 0.32, 0.32
MutPred
0.56
.;.;.;.;Gain of disorder (P = 0.0964);
MVP
0.84
MPC
0.23
ClinPred
0.032
T
GERP RS
0.46
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.41
gMVP
0.74

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.

Other links and lift over

dbSNP: rs1051519; hg19: chr4-108940732; COSMIC: COSV99067156; API