rs12470652

Positions:

chr2-48694299-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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. 12/20 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:6

Conservation

PhyloP100: 3.13

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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 id is 138116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-48694299-T-C is described in Lovd as [Likely_benign].

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/exons	MANE	Protein	UniProt
LHCGR	NM_000233.4 linkuse as main transcript	c.872A>G	p.Asn291Ser	missense_variant	10/11	ENST00000294954.12	NP_000224.2	P22888-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LHCGR	ENST00000294954.12 linkuse as main transcript	c.872A>G	p.Asn291Ser	missense_variant	10/11	1	NM_000233.4	ENSP00000294954.6	P22888-1
ENSG00000279956	ENST00000602369.3 linkuse as main transcript	n.*145A>G		non_coding_transcript_exon_variant	9/13	5		ENSP00000473498.1	R4GN57
ENSG00000279956	ENST00000602369.3 linkuse as main transcript	n.*145A>G		3_prime_UTR_variant	9/13	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

GnomAD3 exomes

AF:

0.0380

AC:

8953

AN:

235680

Hom.:

233

AF XY:

0.0386

AC XY:

4897

AN XY:

126870

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 SAS exome

AF:

0.0128

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

Gnomad4 AFR exome

AF:

0.00981

Gnomad4 AMR exome

AF:

0.0195

Gnomad4 ASJ exome

AF:

0.0413

Gnomad4 EAS exome

AF:

0.000152

Gnomad4 SAS exome

AF:

0.0129

Gnomad4 FIN exome

AF:

0.0628

Gnomad4 NFE exome

AF:

0.0558

Gnomad4 OTH exome

AF:

0.0422

GnomAD4 genome

AF:

0.0375

AC:

5705

AN:

152286

Hom.:

139

Cov.:

AF XY:

0.0364

AC XY:

2711

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0121

Gnomad4 AMR

AF:

0.0258

Gnomad4 ASJ

AF:

0.0386

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0124

Gnomad4 FIN

AF:

0.0657

Gnomad4 NFE

AF:

0.0559

Gnomad4 OTH

AF:

0.0312

Alfa

AF:

0.0486

Hom.:

445

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:6

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	Jan 22, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2014

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. -

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

Apr 27, 2017

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

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;.;.

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

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