4-108027694-C-A

Position:

• chr4-108027694-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_005327.7(HADH):​c.643C>A​(p.Pro215Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00302 in 1,603,218 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (14 hom.)
• Consequence: HADH NM_005327.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5 O:1
• Conservation: PhyloP100: 6.17

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]

HADH (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.05675757).
• BP6: Variant 4-108027694-C-A is Benign according to our data. Variant chr4-108027694-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 549514.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=4, Uncertain_risk_allele=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00246 (374/152220) while in subpopulation NFE AF= 0.00372 (253/68004). AF 95% confidence interval is 0.00334. There are 1 homozygotes in gnomad4. There are 173 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HADH	NM_005327.7	c.643C>A	p.Pro215Thr	missense_variant	6/8	ENST00000309522.8	NP_005318.6
HADH	NM_001184705.4	c.643C>A	p.Pro215Thr	missense_variant	6/9		NP_001171634.3
HADH	NM_001331027.2	c.655C>A	p.Pro219Thr	missense_variant	6/8		NP_001317956.2
HADH	XR_007096395.1	n.687C>A		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8	c.643C>A	p.Pro215Thr	missense_variant	6/8	1	NM_005327.7	ENSP00000312288.4

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 374 AN: 152102 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00372

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00183 AC: 459 AN: 251450 Hom.: 2 AF XY: 0.00170 AC XY: 231 AN XY: 135898

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00308 AC: 4465 AN: 1450998 Hom.: 14 Cov.: 27 AF XY: 0.00298 AC XY: 2153 AN XY: 722762

Gnomad4 AFR exome AF: 0.000571

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.00104

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.000523

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00375

Gnomad4 OTH exome AF: 0.00278

GnomAD4 genome AF: 0.00246 AC: 374 AN: 152220 Hom.: 1 Cov.: 32 AF XY: 0.00232 AC XY: 173 AN XY: 74422

Gnomad4 AFR AF: 0.000747

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00372

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00286 Hom.: 6

Bravo AF: 0.00266

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00167 AC: 203

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of 3-hydroxyacyl-CoA dehydrogenase Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	HADH: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32876354, 25007923) -

Deficiency of 3-hydroxyacyl-CoA dehydrogenase;C1864948:Hyperinsulinemic hypoglycemia, familial, 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Monogenic diabetes Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Mar 31, 2017

ACMG Criteria:PP3 (11 predictors), BS2 (18 cases and 25 controls in type2diabetesgenetics.org for AD monogenic diabetes; two homozygotes in ExAC) -

Hyperinsulinemic hypoglycemia, familial, 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 03, 2021

This sequence change does not appear to have been previously described in individuals with HADH-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.014% (dbSNP rs140413151). The p.Pro215Thr change affects a highly conserved amino acid residue located in a domain of the HADH protein that is not known to be functional. The p.Pro215Thr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Pro215Thr change remains unknown at this time. -

HADH-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 11, 2022

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). -

Hyperinsulinemic hypoglycemia Other:1

Uncertain risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations in HADH gene are associated with congenital hyperinsulinism, which leads to recurrent hypoglycemia. The condition is exacerbated by stress, fasting or excessive dietary protein. May respond well to diazoxide. However, the role of this particular variant rs140413151 in congenital hyperinsulinism is yet to be ascertained. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	.;.;D;.;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.057	T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	.;M;M;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.3	.;.;D;.;D;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	.;.;D;.;D;.
Sift4G	Uncertain	0.023	.;D;D;.;.;D
Polyphen		1.0	.;.;D;.;.;.
Vest4		0.83, 0.84, 0.84
MVP		0.98
MPC		0.89
ClinPred		0.11	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs140413151; hg19: chr4-108948850;