chr4-108023948-A-G

Variant names:

• chr4-108023948-A-G
• rs732941
• NM_005327.7:c.636+385A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005327.7(HADH):​c.636+385A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.774 in 188,492 control chromosomes in the GnomAD database, including 59,478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.75 (45923 hom., cov: 32)
  • Exomes 𝑓: 0.86 (13555 hom.)
• Consequence: HADH NM_005327.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.25
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 4-108023948-A-G is Benign according to our data. Variant chr4-108023948-A-G is described in ClinVar as Benign. ClinVar VariationId is 1279664.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.938 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HADH	NM_005327.7	c.636+385A>G		intron_variant	Intron 5 of 7	ENST00000309522.8	NP_005318.6
HADH	NM_001184705.4	c.636+385A>G		intron_variant	Intron 5 of 8		NP_001171634.3
HADH	NM_001331027.2	c.648+385A>G		intron_variant	Intron 5 of 7		NP_001317956.2
HADH	XR_007096395.1	n.680+385A>G		intron_variant	Intron 5 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8	c.636+385A>G		intron_variant	Intron 5 of 7	1	NM_005327.7	ENSP00000312288.4

Frequencies

GnomAD3 genomes AF: 0.755 AC: 114800 AN: 152062 Hom.: 45913 Cov.: 32

Gnomad AFR AF: 0.463

Gnomad AMI AF: 0.832

Gnomad AMR AF: 0.851

Gnomad ASJ AF: 0.901

Gnomad EAS AF: 0.960

Gnomad SAS AF: 0.861

Gnomad FIN AF: 0.887

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.857

Gnomad OTH AF: 0.784

GnomAD4 exome AF: 0.856 AC: 31084 AN: 36312 Hom.: 13555 Cov.: 0 AF XY: 0.857 AC XY: 16480 AN XY: 19226

African (AFR) AF: 0.434 AC: 744 AN: 1714

American (AMR) AF: 0.893 AC: 2977 AN: 3334

Ashkenazi Jewish (ASJ) AF: 0.909 AC: 773 AN: 850

East Asian (EAS) AF: 0.966 AC: 2930 AN: 3032

South Asian (SAS) AF: 0.852 AC: 3760 AN: 4412

European-Finnish (FIN) AF: 0.909 AC: 838 AN: 922

Middle Eastern (MID) AF: 0.798 AC: 67 AN: 84

European-Non Finnish (NFE) AF: 0.865 AC: 17459 AN: 20186

Other (OTH) AF: 0.864 AC: 1536 AN: 1778

GnomAD4 genome AF: 0.755 AC: 114851 AN: 152180 Hom.: 45923 Cov.: 32 AF XY: 0.761 AC XY: 56616 AN XY: 74404

African (AFR) AF: 0.463 AC: 19207 AN: 41492

American (AMR) AF: 0.851 AC: 13017 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.901 AC: 3128 AN: 3472

East Asian (EAS) AF: 0.960 AC: 4971 AN: 5178

South Asian (SAS) AF: 0.862 AC: 4155 AN: 4822

European-Finnish (FIN) AF: 0.887 AC: 9397 AN: 10590

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.857 AC: 58299 AN: 68014

Other (OTH) AF: 0.786 AC: 1664 AN: 2116

Alfa AF: 0.667 Hom.: 3228

Bravo AF: 0.741

Asia WGS AF: 0.886 AC: 3081 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.2
DANN	Benign	0.40
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs732941; hg19: chr4-108945104;