4-108014612-CTTTT-CTTTTT

Variant names:

• chr4-108014612-C-CT
• rs550348868
• NM_005327.7:c.419+39dupT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005327.7(HADH):​c.419+39dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,268,284 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (0 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: Uncertain_significance. The variant received 0 ACMG points.

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

Frequencies

GnomAD3 genomes AF: 0.0000206 AC: 3 AN: 145882 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000510

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: 0.0000151

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000655 AC: 80 AN: 122084 AF XY: 0.000582

Gnomad AFR exome AF: 0.00462

Gnomad AMR exome AF: 0.0000687

Gnomad ASJ exome AF: 0.000225

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000482

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00195 AC: 2190 AN: 1122402 Hom.: 0 Cov.: 0 AF XY: 0.00178 AC XY: 1000 AN XY: 562640

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

African (AFR) AF: 0.00939 AC: 237 AN: 25246

American (AMR) AF: 0.000142 AC: 5 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.000329 AC: 7 AN: 21256

East Asian (EAS) AF: 0.000278 AC: 9 AN: 32384

South Asian (SAS) AF: 0.000974 AC: 68 AN: 69810

European-Finnish (FIN) AF: 0.000186 AC: 8 AN: 43074

Middle Eastern (MID) AF: 0.00106 AC: 5 AN: 4716

European-Non Finnish (NFE) AF: 0.00208 AC: 1753 AN: 843834

Other (OTH) AF: 0.00209 AC: 98 AN: 46880

⚠️ 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: 0.0000206 AC: 3 AN: 145882 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 70800

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

African (AFR) AF: 0.0000510 AC: 2 AN: 39190

American (AMR) AF: 0.00 AC: 0 AN: 14668

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5040

South Asian (SAS) AF: 0.00 AC: 0 AN: 4600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66352

Other (OTH) AF: 0.00 AC: 0 AN: 1988

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0245704), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 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;