NM_005327.7:c.419+38_419+39delTT

Variant names:

• chr4-108014612-CTT-C
• rs550348868
• NM_005327.7:c.419+38_419+39delTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_005327.7(HADH):​c.419+38_419+39delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,238,718 control chromosomes in the GnomAD database, including 6 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0025 (6 hom.)
• Consequence: HADH NM_005327.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

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.419+38_419+39delTT		intron	N/A	NP_005318.6
	HADH	NM_001184705.4		c.419+38_419+39delTT		intron	N/A	NP_001171634.3
	HADH	NM_001331027.2		c.431+38_431+39delTT		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.419+38_419+39delTT		intron	N/A	ENSP00000312288.4
	HADH	ENST00000505878.4	TSL:1	c.596+38_596+39delTT		intron	N/A	ENSP00000425952.2
	HADH	ENST00000603302.5	TSL:1	c.419+38_419+39delTT		intron	N/A	ENSP00000474560.1

Frequencies

GnomAD3 genomes AF: 0.0000274 AC: 4 AN: 145798 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000255

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: 0.000213

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000151

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00169 AC: 206 AN: 122084 AF XY: 0.00165

Gnomad AFR exome AF: 0.000660

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00180

Gnomad EAS exome AF: 0.00152

Gnomad FIN exome AF: 0.00169

Gnomad NFE exome AF: 0.00158

Gnomad OTH exome AF: 0.00394

GnomAD4 exome AF: 0.00250 AC: 2737 AN: 1092856 Hom.: 6 AF XY: 0.00221 AC XY: 1213 AN XY: 548252

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00430 AC: 106 AN: 24648

American (AMR) AF: 0.00156 AC: 54 AN: 34658

Ashkenazi Jewish (ASJ) AF: 0.00130 AC: 27 AN: 20782

East Asian (EAS) AF: 0.000727 AC: 23 AN: 31630

South Asian (SAS) AF: 0.00113 AC: 78 AN: 68914

European-Finnish (FIN) AF: 0.00145 AC: 61 AN: 42152

Middle Eastern (MID) AF: 0.000650 AC: 3 AN: 4614

European-Non Finnish (NFE) AF: 0.00279 AC: 2288 AN: 819810

Other (OTH) AF: 0.00212 AC: 97 AN: 45648

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000274 AC: 4 AN: 145862 Hom.: 0 Cov.: 29 AF XY: 0.0000565 AC XY: 4 AN XY: 70830

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000255 AC: 1 AN: 39264

American (AMR) AF: 0.00 AC: 0 AN: 14678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.00 AC: 0 AN: 5026

South Asian (SAS) AF: 0.00 AC: 0 AN: 4590

European-Finnish (FIN) AF: 0.000213 AC: 2 AN: 9390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66306

Other (OTH) AF: 0.00 AC: 0 AN: 2006

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00245 Hom.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs550348868; hg19: chr4-108935768; COSMIC: COSV58848390;