rs375717077

Positions:

• chr4-108027757-C-G
• chr4-108027757-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005327.7(HADH):​c.706C>G​(p.Arg236Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: HADH NM_005327.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.40

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HADH	NM_005327.7	c.706C>G	p.Arg236Gly	missense_variant	6/8	ENST00000309522.8	NP_005318.6
HADH	NM_001184705.4	c.706C>G	p.Arg236Gly	missense_variant	6/9		NP_001171634.3
HADH	NM_001331027.2	c.718C>G	p.Arg240Gly	missense_variant	6/8		NP_001317956.2
HADH	XR_007096395.1	n.750C>G		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8	c.706C>G	p.Arg236Gly	missense_variant	6/8	1	NM_005327.7	ENSP00000312288	P4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 26

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74284

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	.;.;D;.;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.42	T;T;D;D;T;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.4	.;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.8	.;.;D;.;D;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	.;.;D;.;D;.
Sift4G	Uncertain	0.0030	.;D;D;.;.;D
Polyphen		1.0	.;.;D;.;.;.
Vest4		0.83, 0.91, 0.92
MutPred		0.62		.;.;.;.;.;Loss of stability (P = 0.0404);
MVP		0.97
MPC		0.99
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.95
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.37		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs375717077; hg19: chr4-108948913;