rs140413151

Variant names:

• chr4-108027694-C-A
• rs140413151
• NM_005327.7:c.643C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-108027694-C-A
• chr4-108027694-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_005327.7(HADH):​c.643C>A​(p.Pro215Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00302 in 1,603,218 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P215S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (14 hom.)
• Consequence: HADH NM_005327.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:7 O:1
• Conservation: PhyloP100: 6.17
• Publications: 12 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 -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.05675757).
• BP6: Variant 4-108027694-C-A is Benign according to our data. Variant chr4-108027694-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 549514.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00246 (374/152220) while in subpopulation NFE AF = 0.00372 (253/68004). AF 95% confidence interval is 0.00334. There are 1 homozygotes in GnomAd4. There are 173 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADH	NM_005327.7	MANE Select	c.643C>A	p.Pro215Thr	missense	Exon 6 of 8	NP_005318.6
	HADH	NM_001184705.4		c.643C>A	p.Pro215Thr	missense	Exon 6 of 9	NP_001171634.3
	HADH	NM_001331027.2		c.655C>A	p.Pro219Thr	missense	Exon 6 of 8	NP_001317956.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADH	ENST00000309522.8	TSL:1 MANE Select	c.643C>A	p.Pro215Thr	missense	Exon 6 of 8	ENSP00000312288.4
	HADH	ENST00000505878.4	TSL:1	c.820C>A	p.Pro274Thr	missense	Exon 6 of 9	ENSP00000425952.2
	HADH	ENST00000603302.5	TSL:1	c.643C>A	p.Pro215Thr	missense	Exon 6 of 9	ENSP00000474560.1

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 374 AN: 152102 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00372

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00183 AC: 459 AN: 251450 AF XY: 0.00170

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00308 AC: 4465 AN: 1450998 Hom.: 14 Cov.: 27 AF XY: 0.00298 AC XY: 2153 AN XY: 722762

African (AFR) AF: 0.000571 AC: 19 AN: 33290

American (AMR) AF: 0.00150 AC: 67 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00104 AC: 27 AN: 26042

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39638

South Asian (SAS) AF: 0.000523 AC: 45 AN: 86052

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53400

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5752

European-Non Finnish (NFE) AF: 0.00375 AC: 4131 AN: 1102052

Other (OTH) AF: 0.00278 AC: 167 AN: 60060

GnomAD4 genome AF: 0.00246 AC: 374 AN: 152220 Hom.: 1 Cov.: 32 AF XY: 0.00232 AC XY: 173 AN XY: 74422

African (AFR) AF: 0.000747 AC: 31 AN: 41524

American (AMR) AF: 0.00190 AC: 29 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00372 AC: 253 AN: 68004

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00279 Hom.: 8

Bravo AF: 0.00266

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00167 AC: 203

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00302

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.057	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		6.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.98
MPC		0.89
ClinPred		0.11	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.96
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs140413151; hg19: chr4-108948850;