3-172633536-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_020792.6(NCEH1):c.1166A>G(p.Asn389Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

NCEH1
NM_020792.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.94

Variant links:

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]

NCEH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity NCEH1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07291752).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NCEH1	NM_020792.6 linkuse as main transcript	c.1166A>G	p.Asn389Ser	missense_variant	5/5	ENST00000475381.7
NCEH1	NM_001146276.3 linkuse as main transcript	c.1190A>G	p.Asn397Ser	missense_variant	5/5
NCEH1	NM_001146277.3 linkuse as main transcript	c.767A>G	p.Asn256Ser	missense_variant	5/5
NCEH1	NM_001146278.3 linkuse as main transcript	c.767A>G	p.Asn256Ser	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCEH1	ENST00000475381.7 linkuse as main transcript	c.1166A>G	p.Asn389Ser	missense_variant	5/5	1	NM_020792.6	P1	Q6PIU2-1
NCEH1	ENST00000538775.5 linkuse as main transcript	c.1286A>G	p.Asn429Ser	missense_variant	5/5	2
NCEH1	ENST00000543711.5 linkuse as main transcript	c.767A>G	p.Asn256Ser	missense_variant	4/4	2			Q6PIU2-3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251456

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2022

The c.1286A>G (p.N429S) alteration is located in exon 5 (coding exon 5) of the NCEH1 gene. This alteration results from a A to G substitution at nucleotide position 1286, causing the asparagine (N) at amino acid position 429 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

Cadd

Benign

Dann

Benign

0.91

DEOGEN2

Benign

0.039

T;.;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.81

T;T;D

M_CAP

Benign

0.0042

MetaRNN

Benign

0.073

T;T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

0.93

N;N;N;N

PrimateAI

Benign

0.37

REVEL

Benign

0.075

Sift4G

Benign

0.40

T;T;T

Vest4

0.23

MVP

0.26

MPC

0.30

ClinPred

0.095

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.38

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over