rs2293275

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The ENST00000294954.12(LHCGR):c.935A>G(p.Asn312Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.582 in 1,565,618 control chromosomes in the GnomAD database, including 273,076 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 22631 hom., cov: 33)

Exomes 𝑓: 0.59 ( 250445 hom. )

Consequence

LHCGR
ENST00000294954.12 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.19

Variant links:

Genes affected

LHCGR (HGNC:6585): (luteinizing hormone/choriogonadotropin receptor) This gene encodes the receptor for both luteinizing hormone and choriogonadotropin. This receptor belongs to the G-protein coupled receptor 1 family, and its activity is mediated by G proteins which activate adenylate cyclase. Mutations in this gene result in disorders of male secondary sexual character development, including familial male precocious puberty, also known as testotoxicosis, hypogonadotropic hypogonadism, Leydig cell adenoma with precocious puberty, and male pseudohermaphtoditism with Leydig cell hypoplasia. [provided by RefSeq, Jul 2008]

LHCGR links:

STON1-GTF2A1L (HGNC:):

STON1-GTF2A1L links:

GTF2A1L (HGNC:30727): (general transcription factor IIA subunit 1 like) The assembly and stability of the RNA polymerase II transcription pre-initiation complex on a eukaryotic core promoter involve the effects of transcription factor IIA (TFIIA) on the interaction between TATA-binding protein (TBP) and DNA. This gene encodes a germ cell-specific counterpart of the large (alpha/beta) subunit of general transcription factor TFIIA that is able to stabilize the binding of TBP to DNA and may be uniquely important to testis biology. Alternative splicing for this locus has been observed and two variants, encoding distinct isoforms, have been identified. Co-transcription of this gene and the neighboring upstream gene generates a rare transcript (SALF), which encodes a fusion protein comprised of sequence sharing identity with each individual gene product. [provided by RefSeq, Mar 2014]

GTF2A1L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 2-48694236-T-C is Benign according to our data. Variant chr2-48694236-T-C is described in ClinVar as [Benign]. Clinvar id is 255609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-48694236-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.91 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHCGR	NM_000233.4 linkuse as main transcript	c.935A>G	p.Asn312Ser	missense_variant	10/11	ENST00000294954.12	NP_000224.2
STON1-GTF2A1L	NM_001198593.2 linkuse as main transcript	c.3441+22556T>C		intron_variant			NP_001185522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHCGR	ENST00000294954.12 linkuse as main transcript	c.935A>G	p.Asn312Ser	missense_variant	10/11	1	NM_000233.4	ENSP00000294954	A2	P22888-1

Frequencies

GnomAD3 genomes

AF:

0.524

AC:

79577

AN:

151958

Hom.:

22629

Cov.:

show subpopulations

Gnomad AFR

AF:

0.298

Gnomad AMI

AF:

0.491

Gnomad AMR

AF:

0.635

Gnomad ASJ

AF:

0.644

Gnomad EAS

AF:

0.932

Gnomad SAS

AF:

0.619

Gnomad FIN

AF:

0.580

Gnomad MID

AF:

0.649

Gnomad NFE

AF:

0.581

Gnomad OTH

AF:

0.568

GnomAD3 exomes

AF:

0.613

AC:

143913

AN:

234642

Hom.:

46054

AF XY:

0.613

AC XY:

77420

AN XY:

126368

show subpopulations

Gnomad AFR exome

AF:

0.287

Gnomad AMR exome

AF:

0.707

Gnomad ASJ exome

AF:

0.670

Gnomad EAS exome

AF:

0.930

Gnomad SAS exome

AF:

0.612

Gnomad FIN exome

AF:

0.572

Gnomad NFE exome

AF:

0.582

Gnomad OTH exome

AF:

0.621

GnomAD4 exome

AF:

0.589

AC:

832319

AN:

1413542

Hom.:

250445

Cov.:

AF XY:

0.590

AC XY:

415494

AN XY:

704166

show subpopulations

Gnomad4 AFR exome

AF:

0.291

Gnomad4 AMR exome

AF:

0.697

Gnomad4 ASJ exome

AF:

0.663

Gnomad4 EAS exome

AF:

0.937

Gnomad4 SAS exome

AF:

0.612

Gnomad4 FIN exome

AF:

0.573

Gnomad4 NFE exome

AF:

0.577

Gnomad4 OTH exome

AF:

0.603

GnomAD4 genome

AF:

0.523

AC:

79610

AN:

152076

Hom.:

22631

Cov.:

AF XY:

0.531

AC XY:

39499

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.298

Gnomad4 AMR

AF:

0.635

Gnomad4 ASJ

AF:

0.644

Gnomad4 EAS

AF:

0.932

Gnomad4 SAS

AF:

0.620

Gnomad4 FIN

AF:

0.580

Gnomad4 NFE

AF:

0.581

Gnomad4 OTH

AF:

0.568

Alfa

AF:

0.586

Hom.:

66336

Bravo

AF:

0.522

TwinsUK

AF:

0.575

AC:

2131

ALSPAC

AF:

0.590

AC:

2272

ESP6500AA

AF:

0.297

AC:

1307

ESP6500EA

AF:

0.591

AC:

5074

ExAC

AF:

0.592

AC:

71626

Asia WGS

AF:

0.707

AC:

2459

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 26662070, 22882535, 24792890, 22356187) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypergonadotropic hypogonadism

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Leydig cell agenesis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Gonadotropin-independent familial sexual precocity

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.078

T;.;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.62

T;T;T

MetaRNN

Benign

9.4e-7

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.73

N;.;.

MutationTaster

Benign

0.62

P;P;P;P;P;P

PrimateAI

Benign

0.33

PROVEAN

Benign

0.080

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.72

T;T;T

Sift4G

Benign

0.77

T;T;T

Polyphen

0.0040

B;.;.

Vest4

0.067

MPC

0.068

ClinPred

0.0051

GERP RS

3.9

Varity_R

0.043

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.35

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