chr1-200048706-G-C

Position:

chr1-200048706-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000367362.8(NR5A2):c.998G>C(p.Arg333Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,614,146 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R333Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 46 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 46 hom. )

Consequence

NR5A2
ENST00000367362.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 9.43

Variant links:

Genes affected

NR5A2 (HGNC:7984): (nuclear receptor subfamily 5 group A member 2) The protein encoded by this gene is a DNA-binding zinc finger transcription factor and is a member of the fushi tarazu factor-1 subfamily of orphan nuclear receptors. The encoded protein is involved in the expression of genes for hepatitis B virus and cholesterol biosynthesis, and may be an important regulator of embryonic development. [provided by RefSeq, Jun 2016]

NR5A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005218625).

BP6

Variant 1-200048706-G-C is Benign according to our data. Variant chr1-200048706-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 786993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0137 (2093/152256) while in subpopulation AFR AF= 0.046 (1909/41544). AF 95% confidence interval is 0.0442. There are 46 homozygotes in gnomad4. There are 991 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2093 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR5A2	NM_205860.3 linkuse as main transcript	c.998G>C	p.Arg333Pro	missense_variant	5/8	ENST00000367362.8	NP_995582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR5A2	ENST00000367362.8 linkuse as main transcript	c.998G>C	p.Arg333Pro	missense_variant	5/8	1	NM_205860.3	ENSP00000356331	A1	O00482-1
NR5A2	ENST00000236914.7 linkuse as main transcript	c.860G>C	p.Arg287Pro	missense_variant	4/7	1		ENSP00000236914	A1	O00482-2
NR5A2	ENST00000367357.3 linkuse as main transcript	c.761G>C	p.Arg254Pro	missense_variant	3/4	1		ENSP00000356326
NR5A2	ENST00000544748.5 linkuse as main transcript	c.782G>C	p.Arg261Pro	missense_variant	4/7	2		ENSP00000439116	P4	O00482-4

Frequencies

GnomAD3 genomes

AF:

0.0137

AC:

2091

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0460

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00648

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.00416

AC:

1047

AN:

251448

Hom.:

AF XY:

0.00322

AC XY:

438

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0474

Gnomad AMR exome

AF:

0.00413

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000832

Gnomad NFE exome

AF:

0.000809

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00167

AC:

2435

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

1131

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0429

Gnomad4 AMR exome

AF:

0.00463

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.000618

Gnomad4 NFE exome

AF:

0.000459

Gnomad4 OTH exome

AF:

0.00353

GnomAD4 genome

AF:

0.0137

AC:

2093

AN:

152256

Hom.:

Cov.:

AF XY:

0.0133

AC XY:

991

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0460

Gnomad4 AMR

AF:

0.00647

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00993

Alfa

AF:

0.000986

Hom.:

Bravo

AF:

0.0156

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0461

AC:

203

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00504

AC:

612

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000818

EpiControl

AF:

0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 17, 2018	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;.;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.96

D;D;D

MetaRNN

Benign

0.0052

T;T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.6

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.4

D;D;D

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0070

D;D;D

Sift4G

Benign

0.065

T;D;D

Polyphen

1.0

D;.;.

Vest4

0.79

MVP

0.81

MPC

1.4

ClinPred

0.038

GERP RS

5.3

Varity_R

0.95

gMVP

0.73

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