chr3-172645627-T-A

Variant names:

• chr3-172645627-T-A
• rs367986260
• NM_020792.6:c.433A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020792.6(NCEH1):​c.433A>T​(p.Ile145Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. I145V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NCEH1 NM_020792.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• Publications: 0 publications found

Genes affected

NCEH1 (HGNC:29260): (neutral cholesterol ester hydrolase 1) Predicted to enable hydrolase activity. Predicted to be involved in ether lipid metabolic process. Predicted to act upstream of or within SMAD protein signal transduction; protein dephosphorylation; and xenobiotic metabolic process. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.789

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020792.6. 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
	NCEH1	NM_020792.6	MANE Select	c.433A>T	p.Ile145Phe	missense	Exon 3 of 5	NP_065843.4
	NCEH1	NM_001146276.3		c.457A>T	p.Ile153Phe	missense	Exon 3 of 5	NP_001139748.2	Q6PIU2-2
	NCEH1	NM_001146277.3		c.34A>T	p.Ile12Phe	missense	Exon 3 of 5	NP_001139749.1	Q6PIU2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCEH1	ENST00000475381.7	TSL:1 MANE Select	c.433A>T	p.Ile145Phe	missense	Exon 3 of 5	ENSP00000418571.4	Q6PIU2-1
	NCEH1	ENST00000538775.5	TSL:2	c.553A>T	p.Ile185Phe	missense	Exon 3 of 5	ENSP00000442464.1	A0A0A0MTJ9
	NCEH1	ENST00000894447.1		c.433A>T	p.Ile145Phe	missense	Exon 3 of 5	ENSP00000564506.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440422 Hom.: 0 Cov.: 26 AF XY: 0.00000139 AC XY: 1 AN XY: 716996

African (AFR) AF: 0.00 AC: 0 AN: 32916

American (AMR) AF: 0.00 AC: 0 AN: 42472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39190

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098196

Other (OTH) AF: 0.00 AC: 0 AN: 59616

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	0.0017	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-1.1	T
PhyloP100		1.0
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.25
Sift	Uncertain	0.010	D
Sift4G	Benign	0.063	T
Vest4		0.85
MVP		0.60
MPC		1.3
ClinPred		0.98	D
GERP RS		2.6
gMVP		0.81
Mutation Taster		=58/42	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: rs367986260; hg19: chr3-172363417;