Genetic Variant ENST00000457828.6:c.-238G>A (chr21-46228611-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP3BP6_ModerateBS1BS2

The ENST00000457828.6(LSS):c.-238G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000999 in 1,591,286 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00098 ( 3 hom. )

Consequence

LSS
ENST00000457828.6 5_prime_UTR

Scores

Splicing: ADA: 0.9944

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.184

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

BP6

Variant 21-46228611-C-T is Benign according to our data. Variant chr21-46228611-C-T is described in ClinVar as [Benign]. Clinvar id is 1989913.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00119 (181/152298) while in subpopulation AMR AF= 0.00216 (33/15306). AF 95% confidence interval is 0.00158. There are 1 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
LSS	NM_002340.6 link	c.15-12G>A	intron_variant	Intron 1 of 21	ENST00000397728.8	NP_002331.3
LSS	NM_001145437.2 link	c.-238G>A	5_prime_UTR_variant	Exon 1 of 21		NP_001138909.1
LSS	NM_001001438.3 link	c.15-12G>A	intron_variant	Intron 1 of 22		NP_001001438.1
LSS	NM_001145436.2 link	c.15-12G>A	intron_variant	Intron 1 of 21		NP_001138908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8 link	c.15-12G>A		intron_variant	Intron 1 of 21	1	NM_002340.6	ENSP00000380837.2		P48449-1

Frequencies

GnomAD3 genomes

AF:

0.00119

AC:

181

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.0527

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00119

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00123

AC:

254

AN:

205880

Hom.:

AF XY:

0.00120

AC XY:

138

AN XY:

115046

show subpopulations

Gnomad AFR exome

AF:

0.0000826

Gnomad AMR exome

AF:

0.000760

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000845

Gnomad NFE exome

AF:

0.00237

Gnomad OTH exome

AF:

0.000948

GnomAD4 exome

AF:

0.000978

AC:

1408

AN:

1438988

Hom.:

Cov.:

AF XY:

0.000942

AC XY:

674

AN XY:

715826

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.000844

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000797

Gnomad4 NFE exome

AF:

0.00116

Gnomad4 OTH exome

AF:

0.000820

GnomAD4 genome

AF:

0.00119

AC:

181

AN:

152298

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.00119

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000682

Hom.:

Bravo

AF:

0.00142

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.96

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.27

Position offset: -12

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