rs17511214

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-108023576-G-A
• chr4-108023576-G-C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• 3-hydroxyacyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, ClinGen
• hyperinsulinemic hypoglycemia, familial, 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005327.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADH	NM_005327.7	MANE Select	c.636+13G>A		intron	N/A	NP_005318.6
	HADH	NM_001184705.4		c.636+13G>A		intron	N/A	NP_001171634.3
	HADH	NM_001331027.2		c.648+13G>A		intron	N/A	NP_001317956.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADH	ENST00000309522.8	TSL:1 MANE Select	c.636+13G>A		intron	N/A	ENSP00000312288.4
	HADH	ENST00000505878.4	TSL:1	c.813+13G>A		intron	N/A	ENSP00000425952.2
	HADH	ENST00000603302.5	TSL:1	c.636+13G>A		intron	N/A	ENSP00000474560.1

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

GnomAD2 exomes AF: 0.0408 AC: 10262 AN: 251394 AF XY: 0.0413

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 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

African (AFR) AF: 0.00781 AC: 239 AN: 30592

American (AMR) AF: 0.0258 AC: 1150 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.0602 AC: 1513 AN: 25148

East Asian (EAS) AF: 0.0000512 AC: 2 AN: 39026

South Asian (SAS) AF: 0.0197 AC: 1639 AN: 83188

European-Finnish (FIN) AF: 0.0658 AC: 3509 AN: 53332

Middle Eastern (MID) AF: 0.0370 AC: 204 AN: 5512

European-Non Finnish (NFE) AF: 0.0570 AC: 55113 AN: 966666

Other (OTH) AF: 0.0481 AC: 2654 AN: 55192

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

African (AFR) AF: 0.0103 AC: 427 AN: 41566

American (AMR) AF: 0.0412 AC: 631 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0700 AC: 243 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4828

European-Finnish (FIN) AF: 0.0700 AC: 742 AN: 10594

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0570 AC: 3875 AN: 68016

Other (OTH) AF: 0.0507 AC: 107 AN: 2110

Alfa AF: 0.0482 Hom.: 101

Bravo AF: 0.0372

Asia WGS AF: 0.0100 AC: 35 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Deficiency of 3-hydroxyacyl-CoA dehydrogenase (2)
-	-	2	not provided (2)
-	-	1	Hyperinsulinemic hypoglycemia, familial, 1 (1)
-	-	1	Hyperinsulinemic hypoglycemia, familial, 4 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.71
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17511214; hg19: chr4-108944732;