4-108014518-G-C

Position:

• chr4-108014518-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PS1 BP4 BS1_Supporting BS2

The NM_005327.7(HADH):​c.349G>C​(p.Val117Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00039 in 1,614,002 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (2 hom.)
• Consequence: HADH NM_005327.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.60

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 Likely_benign. Variant got -2 ACMG points.

• PS1: Transcript NM_005327.7 (HADH) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• BP4: Computational evidence support a benign effect (MetaRNN=0.28926376).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000397 (581/1461830) while in subpopulation NFE AF= 0.000499 (555/1111956). AF 95% confidence interval is 0.000464. There are 2 homozygotes in gnomad4_exome. There are 292 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HADH	NM_005327.7	c.349G>C	p.Val117Leu	missense_variant	3/8	ENST00000309522.8	NP_005318.6
HADH	NM_001184705.4	c.349G>C	p.Val117Leu	missense_variant	3/9		NP_001171634.3
HADH	NM_001331027.2	c.361G>C	p.Val121Leu	missense_variant	3/8		NP_001317956.2
HADH	XR_007096395.1	n.393G>C		non_coding_transcript_exon_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8	c.349G>C	p.Val117Leu	missense_variant	3/8	1	NM_005327.7	ENSP00000312288.4

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

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: 0.000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000298 AC: 75 AN: 251492 Hom.: 0 AF XY: 0.000294 AC XY: 40 AN XY: 135920

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

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: 0.000589

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000397 AC: 581 AN: 1461830 Hom.: 2 Cov.: 32 AF XY: 0.000402 AC XY: 292 AN XY: 727228

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000749

Gnomad4 NFE exome AF: 0.000499

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74328

Gnomad4 AFR AF: 0.000217

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: 0.000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000402 Hom.: 0

Bravo AF: 0.000227

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000709

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of 3-hydroxyacyl-CoA dehydrogenase Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 06, 2022	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 117 of the HADH protein (p.Val117Leu). This variant is present in population databases (rs146732064, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with HADH-related conditions. ClinVar contains an entry for this variant (Variation ID: 652881). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 22, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Hyperinsulinemic hypoglycemia Uncertain:1

Uncertain significance, 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 rs146732064 in congenital hyperinsulinism is yet to be ascertained. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

HADH: PM2, PS1:Moderate, BP4 -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	.;.;T;.;.
Eigen	Benign	0.025
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.8	.;L;L;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.6	.;.;N;N;.
REVEL	Benign	0.26
Sift	Benign	0.22	.;.;T;T;.
Sift4G	Benign	0.11	.;T;T;.;T
Polyphen		0.0050	.;.;B;.;.
Vest4		0.35, 0.35, 0.34
MutPred		0.80		.;.;.;.;Loss of sheet (P = 0.0817);
MVP		0.77
MPC		0.24
ClinPred		0.047	T
GERP RS		4.9
Varity_R		0.45
gMVP		0.66

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: rs146732064; hg19: chr4-108935674;