NM_005327.7:c.636+13G>A

Variant names:

• chr4-108023576-G-A
• rs17511214
• NM_005327.7:c.636+13G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005327.7(HADH):​c.636+13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0496 in 1,455,470 control chromosomes in the GnomAD database, including 2,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (131 hom., cov: 33)
  • Exomes 𝑓: 0.051 (1919 hom.)
• Consequence: HADH NM_005327.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.15

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 4-108023576-G-A is Benign according to our data. Variant chr4-108023576-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HADH	NM_005327.7	c.636+13G>A		intron_variant	Intron 5 of 7	ENST00000309522.8	NP_005318.6
HADH	NM_001184705.4	c.636+13G>A		intron_variant	Intron 5 of 8		NP_001171634.3
HADH	NM_001331027.2	c.648+13G>A		intron_variant	Intron 5 of 7		NP_001317956.2
HADH	XR_007096395.1	n.680+13G>A		intron_variant	Intron 5 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8	c.636+13G>A		intron_variant	Intron 5 of 7	1	NM_005327.7	ENSP00000312288.4

Frequencies

GnomAD3 genomes AF: 0.0406 AC: 6181 AN: 152160 Hom.: 132 Cov.: 33

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0413

Gnomad ASJ AF: 0.0700

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.0700

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0570

Gnomad OTH AF: 0.0512

GnomAD3 exomes AF: 0.0408 AC: 10262 AN: 251394 Hom.: 290 AF XY: 0.0413 AC XY: 5616 AN XY: 135866

Gnomad AFR exome AF: 0.00733

Gnomad AMR exome AF: 0.0233

Gnomad ASJ exome AF: 0.0636

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0198

Gnomad FIN exome AF: 0.0666

Gnomad NFE exome AF: 0.0562

Gnomad OTH exome AF: 0.0417

GnomAD4 exome AF: 0.0507 AC: 66023 AN: 1303194 Hom.: 1919 Cov.: 20 AF XY: 0.0499 AC XY: 32770 AN XY: 656988

Gnomad4 AFR exome AF: 0.00781

Gnomad4 AMR exome AF: 0.0258

Gnomad4 ASJ exome AF: 0.0602

Gnomad4 EAS exome AF: 0.0000512

Gnomad4 SAS exome AF: 0.0197

Gnomad4 FIN exome AF: 0.0658

Gnomad4 NFE exome AF: 0.0570

Gnomad4 OTH exome AF: 0.0481

GnomAD4 genome AF: 0.0406 AC: 6178 AN: 152276 Hom.: 131 Cov.: 33 AF XY: 0.0403 AC XY: 2999 AN XY: 74456

Gnomad4 AFR AF: 0.0103

Gnomad4 AMR AF: 0.0412

Gnomad4 ASJ AF: 0.0700

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0199

Gnomad4 FIN AF: 0.0700

Gnomad4 NFE AF: 0.0570

Gnomad4 OTH AF: 0.0507

Alfa AF: 0.0496 Hom.: 38

Bravo AF: 0.0372

Asia WGS AF: 0.0100 AC: 35 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of 3-hydroxyacyl-CoA dehydrogenase Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyperinsulinemic hypoglycemia, familial, 1 Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

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 rs17511214 in congenital hyperinsulinism is yet to be ascertained. -

Hyperinsulinemic hypoglycemia, familial, 4 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17511214; hg19: chr4-108944732;