rs36030668

Variant names:

• chr4-108034293-A-G
• rs36030668
• NM_005327.7:c.881A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005327.7(HADH):​c.881A>G​(p.Asn294Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00121 in 1,613,920 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0068 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (9 hom.)
• Consequence: HADH NM_005327.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications B:7 O:1
• Conservation: PhyloP100: 4.27
• 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: Orphanet, ClinGen, PanelApp Australia
• hyperinsulinemic hypoglycemia, familial, 4

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007502228).
• BP6: Variant 4-108034293-A-G is Benign according to our data. Variant chr4-108034293-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 393393.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00679 (1034/152358) while in subpopulation AFR AF = 0.0239 (993/41588). AF 95% confidence interval is 0.0226. There are 9 homozygotes in GnomAd4. There are 476 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADH	NM_005327.7	MANE Select	c.881A>G	p.Asn294Ser	missense	Exon 8 of 8	NP_005318.6	Q16836-1
	HADH	NM_001184705.4		c.932A>G	p.Asn311Ser	missense	Exon 9 of 9	NP_001171634.3
	HADH	NM_001331027.2		c.893A>G	p.Asn298Ser	missense	Exon 8 of 8	NP_001317956.2	A0A0D9SFP2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADH	ENST00000309522.8	TSL:1 MANE Select	c.881A>G	p.Asn294Ser	missense	Exon 8 of 8	ENSP00000312288.4	Q16836-1
	HADH	ENST00000505878.4	TSL:1	c.1109A>G	p.Asn370Ser	missense	Exon 9 of 9	ENSP00000425952.2	E9PF18
	HADH	ENST00000603302.5	TSL:1	c.932A>G	p.Asn311Ser	missense	Exon 9 of 9	ENSP00000474560.1	Q16836-3

Frequencies

GnomAD3 genomes AF: 0.00675 AC: 1027 AN: 152240 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0238

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

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: 0.0000147

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00180 AC: 453 AN: 251480 AF XY: 0.00120

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000626 AC: 915 AN: 1461562 Hom.: 9 Cov.: 29 AF XY: 0.000532 AC XY: 387 AN XY: 727096

African (AFR) AF: 0.0231 AC: 774 AN: 33468

American (AMR) AF: 0.00125 AC: 56 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111724

Other (OTH) AF: 0.00114 AC: 69 AN: 60376

GnomAD4 genome AF: 0.00679 AC: 1034 AN: 152358 Hom.: 9 Cov.: 33 AF XY: 0.00639 AC XY: 476 AN XY: 74508

African (AFR) AF: 0.0239 AC: 993 AN: 41588

American (AMR) AF: 0.00176 AC: 27 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00268 Hom.: 7

Bravo AF: 0.00778

ESP6500AA AF: 0.0218 AC: 96

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00222 AC: 269

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Deficiency of 3-hydroxyacyl-CoA dehydrogenase (1)
-	-	1	Deficiency of 3-hydroxyacyl-CoA dehydrogenase;C1864948:Hyperinsulinemic hypoglycemia, familial, 4 (1)
-	1	-	Hyperinsulinemic hypoglycemia (1)
-	-	1	Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	-0.16	N
PhyloP100		4.3
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.28
Sift	Benign	0.035	D
Sift4G	Benign	0.38	T
Polyphen		0.0010	B
Vest4		0.10
MVP		0.88
MPC		0.19
ClinPred		0.036	T
GERP RS		3.1
Varity_R		0.13
gMVP		0.82
Mutation Taster		=91/9	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: rs36030668; hg19: chr4-108955449;