chr8-66468293-T-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144650.3(ADHFE1):​c.1345T>A​(p.Cys449Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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: not found (cov: 32)
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09726432).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADHFE1	NM_144650.3	MANE Select	c.1345T>A	p.Cys449Ser	missense	Exon 14 of 14	NP_653251.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADHFE1	ENST00000396623.8	TSL:1 MANE Select	c.1345T>A	p.Cys449Ser	missense	Exon 14 of 14	ENSP00000379865.3
	ADHFE1	ENST00000424777.6	TSL:1	n.*782T>A		non_coding_transcript_exon	Exon 14 of 14	ENSP00000410883.2
	ADHFE1	ENST00000426810.5	TSL:1	n.*1530T>A		non_coding_transcript_exon	Exon 13 of 13	ENSP00000406905.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 56157

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Benign	0.87
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N
PhyloP100		2.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.071
Sift	Benign	0.36	T
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.24
MutPred		0.44		Gain of disorder (P = 0.0022)
MVP		0.15
MPC		0.064
ClinPred		0.27	T
GERP RS		3.7
Varity_R		0.19
gMVP		0.93
Mutation Taster		=96/4	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: rs1060242; hg19: chr8-67380528;