chr8-66468293-T-C

Variant names:

• chr8-66468293-T-C
• rs1060242
• NM_144650.3:c.1345T>C

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. C449Y) has been classified as Uncertain significance.

• 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
• Publications: 58 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144650.3. 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
	ADHFE1	NM_144650.3	MANE Select	c.1345T>C	p.Cys449Arg	missense	Exon 14 of 14	NP_653251.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADHFE1	ENST00000396623.8	TSL:1 MANE Select	c.1345T>C	p.Cys449Arg	missense	Exon 14 of 14	ENSP00000379865.3
	ADHFE1	ENST00000424777.6	TSL:1	n.*782T>C		non_coding_transcript_exon	Exon 14 of 14	ENSP00000410883.2
	ADHFE1	ENST00000426810.5	TSL:1	n.*1530T>C		non_coding_transcript_exon	Exon 13 of 13	ENSP00000406905.1

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

GnomAD2 exomes AF: 0.534 AC: 133170 AN: 249270 AF XY: 0.531

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 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

African (AFR) AF: 0.735 AC: 24472 AN: 33306

American (AMR) AF: 0.648 AC: 28812 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 11949 AN: 26076

East Asian (EAS) AF: 0.414 AC: 16363 AN: 39554

South Asian (SAS) AF: 0.600 AC: 51601 AN: 86064

European-Finnish (FIN) AF: 0.549 AC: 29288 AN: 53340

Middle Eastern (MID) AF: 0.619 AC: 3565 AN: 5756

European-Non Finnish (NFE) AF: 0.476 AC: 528017 AN: 1110308

Other (OTH) AF: 0.514 AC: 30997 AN: 60258

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

African (AFR) AF: 0.721 AC: 29895 AN: 41480

American (AMR) AF: 0.620 AC: 9484 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1570 AN: 3470

East Asian (EAS) AF: 0.410 AC: 2119 AN: 5164

South Asian (SAS) AF: 0.597 AC: 2874 AN: 4816

European-Finnish (FIN) AF: 0.565 AC: 5965 AN: 10550

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.476 AC: 32333 AN: 67978

Other (OTH) AF: 0.575 AC: 1210 AN: 2106

Alfa AF: 0.504 Hom.: 56157

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 v4.9

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
MetaRNN	Benign	0.0000018	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-3.6	N
PhyloP100		2.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	6.2	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	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
Mutation Taster		=97/3	polymorphism (auto)

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