Variant 21-46228579-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_002340.6(LSS):c.35G>A(p.Gly12Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,439,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LSS
NM_002340.6 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.31

Variant links:

Genes affected

LSS (HGNC:6708): (lanosterol synthase) The protein encoded by this gene catalyzes the conversion of (S)-2,3 oxidosqualene to lanosterol. The encoded protein is a member of the terpene cyclase/mutase family and catalyzes the first step in the biosynthesis of cholesterol, steroid hormones, and vitamin D. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Feb 2009]

LSS links:

LSS (HGNC:):

LSS links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 21-46228579-C-T is Pathogenic according to our data. Variant chr21-46228579-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 834068.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LSS	NM_002340.6 linkuse as main transcript	c.35G>A	p.Gly12Asp	missense_variant	2/22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3 linkuse as main transcript	c.35G>A	p.Gly12Asp	missense_variant	2/23		NP_001001438.1
LSS	NM_001145436.2 linkuse as main transcript	c.35G>A	p.Gly12Asp	missense_variant	2/22		NP_001138908.1
LSS	NM_001145437.2 linkuse as main transcript	c.-206G>A		5_prime_UTR_variant	1/21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8 linkuse as main transcript	c.35G>A	p.Gly12Asp	missense_variant	2/22	1	NM_002340.6	ENSP00000380837.2		P48449-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000482

AC:

AN:

207352

Hom.:

AF XY:

0.00000861

AC XY:

AN XY:

116088

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:

0.0000109

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1439794

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716280

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000181

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Alopecia-intellectual disability syndrome 4

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;T;.;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

.;D;D;D

M_CAP

Uncertain

0.086

MetaRNN

Uncertain

0.60

D;D;D;D

MetaSVM

Benign

-0.77

MutationAssessor

Pathogenic

3.0

M;M;M;.

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.7

N;N;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.019

D;D;D;D

Sift4G

Uncertain

0.0070

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.71

MutPred

0.27

Loss of catalytic residue at G12 (P = 0.012);Loss of catalytic residue at G12 (P = 0.012);Loss of catalytic residue at G12 (P = 0.012);.;

MVP

0.67

MPC

1.1

ClinPred

0.98

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.71

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