rs12470652

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000233.4(LHCGR):c.872A>G(p.Asn291Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0477 in 1,591,022 control chromosomes in the GnomAD database, including 2,122 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 139 hom., cov: 33)

Exomes 𝑓: 0.049 ( 1983 hom. )

Consequence

LHCGR
NM_000233.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.13

Publications

32 publications found

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:

ENSG00000279956 (HGNC:):

ENSG00000279956 links:

STON1-GTF2A1L (HGNC:30651): (STON1-GTF2A1L readthrough) STON1-GTF2A1L mRNAs are infrequent but naturally occurring read-through products of the neighboring STON1 and GTF2A1L genes. These transcripts encode fusion proteins composed of the vast majority of each of the individual elements, stonin 1 and general transcription factor IIA, 1-like. Alternative splicing results in multiple transcript variants. The significance of these read-through variants and the function of the resulting protein products have not yet been determined. [provided by RefSeq, Oct 2010]

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 was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.16259 (below the threshold of 3.09). Trascript score misZ: -0.035144 (below the threshold of 3.09). GenCC associations: The gene is linked to Leydig cell hypoplasia, type 1, familial male-limited precocious puberty.

BP4

Computational evidence support a benign effect (MetaRNN=0.002693206).

BP6

Variant 2-48694299-T-C is Benign according to our data. Variant chr2-48694299-T-C is described in ClinVar as Benign. ClinVar VariationId is 138116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0544 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHCGR	NM_000233.4 link	c.872A>G	p.Asn291Ser	missense_variant	Exon 10 of 11	ENST00000294954.12	NP_000224.2	P22888-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LHCGR	ENST00000294954.12 link	c.872A>G	p.Asn291Ser	missense_variant	Exon 10 of 11	1	NM_000233.4	ENSP00000294954.6	P22888-1
ENSG00000279956	ENST00000602369.3 link	n.*145A>G		non_coding_transcript_exon_variant	Exon 9 of 13	5		ENSP00000473498.1	R4GN57
ENSG00000279956	ENST00000602369.3 link	n.*145A>G		3_prime_UTR_variant	Exon 9 of 13	5		ENSP00000473498.1	R4GN57

Frequencies

GnomAD3 genomes

AF:

0.0375

AC:

5707

AN:

152168

Hom.:

139

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0122

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.0258

Gnomad ASJ

AF:

0.0386

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0124

Gnomad FIN

AF:

0.0657

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0559

Gnomad OTH

AF:

0.0315

GnomAD2 exomes

AF:

0.0380

AC:

8953

AN:

235680

AF XY:

0.0386

show subpopulations

Gnomad AFR exome

AF:

0.0113

Gnomad AMR exome

AF:

0.0185

Gnomad ASJ exome

AF:

0.0420

Gnomad EAS exome

AF:

0.000171

Gnomad FIN exome

AF:

0.0652

Gnomad NFE exome

AF:

0.0555

Gnomad OTH exome

AF:

0.0417

GnomAD4 exome

AF:

0.0488

AC:

70217

AN:

1438736

Hom.:

1983

Cov.:

AF XY:

0.0481

AC XY:

34435

AN XY:

715502

show subpopulations

African (AFR)

AF:

0.00981

AC:

326

AN:

33220

American (AMR)

AF:

0.0195

AC:

855

AN:

43796

Ashkenazi Jewish (ASJ)

AF:

0.0413

AC:

1069

AN:

25884

East Asian (EAS)

AF:

0.000152

AC:

AN:

39462

South Asian (SAS)

AF:

0.0129

AC:

1094

AN:

84542

European-Finnish (FIN)

AF:

0.0628

AC:

3322

AN:

52874

Middle Eastern (MID)

AF:

0.0105

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.0558

AC:

60971

AN:

1093616

Other (OTH)

AF:

0.0422

AC:

2514

AN:

59604

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

2680

5360

8039

10719

13399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2194

4388

6582

8776

10970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0375

AC:

5705

AN:

152286

Hom.:

139

Cov.:

AF XY:

0.0364

AC XY:

2711

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0121

AC:

505

AN:

41578

American (AMR)

AF:

0.0258

AC:

394

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0386

AC:

134

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.0124

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0657

AC:

698

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0559

AC:

3802

AN:

67992

Other (OTH)

AF:

0.0312

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

279

558

837

1116

1395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0471

Hom.:

532

Bravo

AF:

0.0339

TwinsUK

AF:

0.0545

AC:

202

ALSPAC

AF:

0.0651

AC:

251

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.0546

AC:

469

ExAC

AF:

0.0365

AC:

4422

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 12, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 18, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hypergonadotropic hypogonadism

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leydig cell agenesis

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Gonadotropin-independent familial sexual precocity

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.086

T;.;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.75

T;T;T

MetaRNN

Benign

0.0027

T;T;T

MetaSVM

Uncertain

0.026

MutationAssessor

Benign

1.3

L;.;.

PhyloP100

3.1

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.19

N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.66

T;T;T

Sift4G

Benign

0.86

T;T;T

Polyphen

1.0

D;.;.

Vest4

0.22

MPC

0.11

ClinPred

0.029

GERP RS

5.4

Varity_R

0.093

gMVP

0.34

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over