4-108014444-T-G

Variant names:

• chr4-108014444-T-G
• rs61735992
• NM_005327.7:c.275T>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005327.7(HADH):​c.275T>G​(p.Phe92Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00649 in 1,614,044 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (56 hom.)
• Consequence: HADH NM_005327.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: 7.59
• Publications: 13 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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.022979915).
• BP6: Variant 4-108014444-T-G is Benign according to our data. Variant chr4-108014444-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00514 (782/152184) while in subpopulation NFE AF = 0.00815 (554/67998). AF 95% confidence interval is 0.00759. There are 6 homozygotes in GnomAd4. There are 389 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.275T>G	p.Phe92Cys	missense	Exon 3 of 8	NP_005318.6
	HADH	NM_001184705.4		c.275T>G	p.Phe92Cys	missense	Exon 3 of 9	NP_001171634.3
	HADH	NM_001331027.2		c.287T>G	p.Phe96Cys	missense	Exon 3 of 8	NP_001317956.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADH	ENST00000309522.8	TSL:1 MANE Select	c.275T>G	p.Phe92Cys	missense	Exon 3 of 8	ENSP00000312288.4
	HADH	ENST00000505878.4	TSL:1	c.452T>G	p.Phe151Cys	missense	Exon 3 of 9	ENSP00000425952.2
	HADH	ENST00000603302.5	TSL:1	c.275T>G	p.Phe92Cys	missense	Exon 3 of 9	ENSP00000474560.1

Frequencies

GnomAD3 genomes AF: 0.00515 AC: 783 AN: 152066 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00540

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00816

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00546 AC: 1374 AN: 251490 AF XY: 0.00574

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00471

Gnomad NFE exome AF: 0.00749

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00664 AC: 9700 AN: 1461860 Hom.: 56 Cov.: 32 AF XY: 0.00676 AC XY: 4915 AN XY: 727234

African (AFR) AF: 0.00149 AC: 50 AN: 33480

American (AMR) AF: 0.00264 AC: 118 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00444 AC: 116 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00747 AC: 644 AN: 86254

European-Finnish (FIN) AF: 0.00429 AC: 229 AN: 53420

Middle Eastern (MID) AF: 0.00624 AC: 36 AN: 5768

European-Non Finnish (NFE) AF: 0.00734 AC: 8157 AN: 1111982

Other (OTH) AF: 0.00578 AC: 349 AN: 60396

GnomAD4 genome AF: 0.00514 AC: 782 AN: 152184 Hom.: 6 Cov.: 32 AF XY: 0.00523 AC XY: 389 AN XY: 74418

African (AFR) AF: 0.00108 AC: 45 AN: 41526

American (AMR) AF: 0.00641 AC: 98 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00541 AC: 26 AN: 4808

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00815 AC: 554 AN: 67998

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00676 Hom.: 16

Bravo AF: 0.00418

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.00532 AC: 646

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00622

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.023	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.038	D
Polyphen		1.0	D
Vest4		0.82
MVP		0.93
MPC		1.0
ClinPred		0.037	T
GERP RS		5.8
Varity_R		0.95
gMVP		0.67
Mutation Taster		=56/44	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: rs61735992; hg19: chr4-108935600; COSMIC: COSV58849932;