Variant 9-124482765-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BP4_Strong

The NM_004959.5(NR5A1):c.1379A>G(p.Gln460Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000362 in 1,298,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q460P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000015 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

NR5A1
NM_004959.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.11

Variant links:

Genes affected

NR5A1 (HGNC:7983): (nuclear receptor subfamily 5 group A member 1) The protein encoded by this gene is a transcriptional activator involved in sex determination. The encoded protein binds DNA as a monomer. Defects in this gene are a cause of XY sex reversal with or without adrenal failure as well as adrenocortical insufficiency without ovarian defect. [provided by RefSeq, Jul 2008]

NR5A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1

In a region_of_interest Important for dimerization (size 231) in uniprot entity STF1_HUMAN there are 48 pathogenic changes around while only 0 benign (100%) in NM_004959.5

BP4

Computational evidence support a benign effect (MetaRNN=0.049322397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR5A1	NM_004959.5 linkuse as main transcript	c.1379A>G	p.Gln460Arg	missense_variant	7/7	ENST00000373588.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NR5A1	ENST00000373588.9 linkuse as main transcript	c.1379A>G	p.Gln460Arg	missense_variant	7/7	1	NM_004959.5	P1
NR5A1	ENST00000620110.4 linkuse as main transcript	c.1259A>G	p.Gln420Arg	missense_variant	6/6	5
NR5A1	ENST00000373587.3 linkuse as main transcript	c.731A>G	p.Gln244Arg	missense_variant	5/5	3

Frequencies

GnomAD3 genomes

AF:

0.0000154

AC:

AN:

129820

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000158

Gnomad OTH

AF:

0.000553

GnomAD3 exomes

AF:

0.00000573

AC:

AN:

174450

Hom.:

AF XY:

0.00

AC XY:

AN XY:

93254

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:

0.0000618

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000385

AC:

AN:

1168598

Hom.:

Cov.:

AF XY:

0.0000418

AC XY:

AN XY:

574570

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000766

Gnomad4 FIN exome

AF:

0.0000346

Gnomad4 NFE exome

AF:

0.0000377

Gnomad4 OTH exome

AF:

0.0000472

GnomAD4 genome

AF:

0.0000154

AC:

AN:

129820

Hom.:

Cov.:

AF XY:

0.0000163

AC XY:

AN XY:

61428

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000158

Gnomad4 OTH

AF:

0.000553

Alfa

AF:

0.0000287

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2020

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29935645) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.28

.;T;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.61

T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.049

T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

-2.6

.;N;.

MutationTaster

Benign

0.59

PrimateAI

Uncertain

0.59

PROVEAN

Benign

1.9

.;N;N

REVEL

Uncertain

0.29

Sift

Benign

1.0

.;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.029

MVP

0.56

MPC

0.79

ClinPred

0.17

GERP RS

3.7

Varity_R

0.58

gMVP

0.059

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