chr8-66468293-T-C

Position:

• chr8-66468293-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_144650.3(ADHFE1):​c.1345T>C​(p.Cys449Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.503 in 1,611,180 control chromosomes in the GnomAD database, including 208,794 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.57 (25361 hom., cov: 32)
  • Exomes 𝑓: 0.50 (183433 hom.)
• Consequence: ADHFE1 NM_144650.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.96

Genes affected

ADHFE1 (HGNC:16354): (alcohol dehydrogenase iron containing 1) The ADHFE1 gene encodes hydroxyacid-oxoacid transhydrogenase (EC 1.1.99.24), which is responsible for the oxidation of 4-hydroxybutyrate in mammalian tissues (Kardon et al., 2006 [PubMed 16616524]).[supplied by OMIM, Mar 2008]

ENSG00000285791 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7892686E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADHFE1	NM_144650.3	c.1345T>C	p.Cys449Arg	missense_variant	14/14	ENST00000396623.8	NP_653251.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADHFE1	ENST00000396623.8	c.1345T>C	p.Cys449Arg	missense_variant	14/14	1	NM_144650.3	ENSP00000379865.3
ENSG00000285791	ENST00000648156.1	n.*540-3137T>C		intron_variant				ENSP00000497007.1

Frequencies

GnomAD3 genomes AF: 0.565 AC: 85840 AN: 151938 Hom.: 25302 Cov.: 32

Gnomad AFR AF: 0.720

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.620

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.410

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.476

Gnomad OTH AF: 0.573

GnomAD3 exomes AF: 0.534 AC: 133170 AN: 249270 Hom.: 36782 AF XY: 0.531 AC XY: 71675 AN XY: 134860

Gnomad AFR exome AF: 0.722

Gnomad AMR exome AF: 0.646

Gnomad ASJ exome AF: 0.467

Gnomad EAS exome AF: 0.404

Gnomad SAS exome AF: 0.603

Gnomad FIN exome AF: 0.556

Gnomad NFE exome AF: 0.477

Gnomad OTH exome AF: 0.547

GnomAD4 exome AF: 0.497 AC: 725064 AN: 1459124 Hom.: 183433 Cov.: 34 AF XY: 0.499 AC XY: 361974 AN XY: 725898

Gnomad4 AFR exome AF: 0.735

Gnomad4 AMR exome AF: 0.648

Gnomad4 ASJ exome AF: 0.458

Gnomad4 EAS exome AF: 0.414

Gnomad4 SAS exome AF: 0.600

Gnomad4 FIN exome AF: 0.549

Gnomad4 NFE exome AF: 0.476

Gnomad4 OTH exome AF: 0.514

GnomAD4 genome AF: 0.565 AC: 85961 AN: 152056 Hom.: 25361 Cov.: 32 AF XY: 0.571 AC XY: 42450 AN XY: 74306

Gnomad4 AFR AF: 0.721

Gnomad4 AMR AF: 0.620

Gnomad4 ASJ AF: 0.452

Gnomad4 EAS AF: 0.410

Gnomad4 SAS AF: 0.597

Gnomad4 FIN AF: 0.565

Gnomad4 NFE AF: 0.476

Gnomad4 OTH AF: 0.575

Alfa AF: 0.492 Hom.: 38861

Bravo AF: 0.575

TwinsUK AF: 0.466 AC: 1729

ALSPAC AF: 0.464 AC: 1788

ESP6500AA AF: 0.718 AC: 3164

ESP6500EA AF: 0.474 AC: 4074

ExAC AF: 0.531 AC: 64446

Asia WGS AF: 0.548 AC: 1906 AN: 3478

EpiCase AF: 0.487

EpiControl AF: 0.492

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Benign	0.88
DEOGEN2	Benign	0.073	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.27	T;T
MetaRNN	Benign	0.0000018	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-3.6	N;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	6.2	N;N
REVEL	Benign	0.14
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.097
MPC		0.090
ClinPred		0.0026	T
GERP RS		3.7
Varity_R		0.34
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060242; hg19: chr8-67380528; COSMIC: COSV52554038; COSMIC: COSV52554038;