4-108000211-G-A

Variant names:

• chr4-108000211-G-A
• rs221330
• NM_005327.7:c.133-9548G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005327.7(HADH):​c.133-9548G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 152,162 control chromosomes in the GnomAD database, including 5,315 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.25 (5315 hom., cov: 32)
• Consequence: HADH NM_005327.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.290

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HADH	NM_005327.7	c.133-9548G>A		intron_variant	Intron 1 of 7	ENST00000309522.8	NP_005318.6
HADH	NM_001184705.4	c.133-9548G>A		intron_variant	Intron 1 of 8		NP_001171634.3
HADH	XR_007096395.1	n.177-9548G>A		intron_variant	Intron 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8	c.133-9548G>A		intron_variant	Intron 1 of 7	1	NM_005327.7	ENSP00000312288.4

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37705 AN: 152044 Hom.: 5308 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.330

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.268

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.248 AC: 37722 AN: 152162 Hom.: 5315 Cov.: 32 AF XY: 0.246 AC XY: 18315 AN XY: 74382

African (AFR) AF: 0.118 AC: 4893 AN: 41534

American (AMR) AF: 0.255 AC: 3903 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1279 AN: 3470

East Asian (EAS) AF: 0.337 AC: 1742 AN: 5168

South Asian (SAS) AF: 0.381 AC: 1837 AN: 4822

European-Finnish (FIN) AF: 0.227 AC: 2406 AN: 10578

Middle Eastern (MID) AF: 0.334 AC: 97 AN: 290

European-Non Finnish (NFE) AF: 0.304 AC: 20674 AN: 67996

Other (OTH) AF: 0.275 AC: 580 AN: 2108

Alfa AF: 0.290 Hom.: 25390

Bravo AF: 0.242

Asia WGS AF: 0.372 AC: 1295 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.87
DANN	Benign	0.41
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

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: rs221330; hg19: chr4-108921367;