rs6755901

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000233.4(LHCGR):c.866+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.819 in 1,612,146 control chromosomes in the GnomAD database, including 546,775 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.81 ( 50083 hom., cov: 32)

Exomes 𝑓: 0.82 ( 496692 hom. )

Consequence

LHCGR
NM_000233.4 splice_region, intron

Scores

Splicing: ADA: 0.00006589

Clinical Significance

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

Conservation

PhyloP100: 0.574

Publications

14 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 2-48698607-C-T is Benign according to our data. Variant chr2-48698607-C-T is described in ClinVar as [Benign]. Clinvar id is 255608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.855 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHCGR	NM_000233.4 link	c.866+8G>A		splice_region_variant, intron_variant	Intron 9 of 10	ENST00000294954.12	NP_000224.2	P22888-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHCGR	ENST00000294954.12 link	c.866+8G>A		splice_region_variant, intron_variant	Intron 9 of 10	1	NM_000233.4	ENSP00000294954.6		P22888-1
ENSG00000279956	ENST00000602369.3 link	n.*139+8G>A		splice_region_variant, intron_variant	Intron 8 of 12	5		ENSP00000473498.1		R4GN57

Frequencies

GnomAD3 genomes

AF:

0.806

AC:

122490

AN:

152000

Hom.:

50033

Cov.:

show subpopulations

Gnomad AFR

AF:

0.862

Gnomad AMI

AF:

0.891

Gnomad AMR

AF:

0.690

Gnomad ASJ

AF:

0.849

Gnomad EAS

AF:

0.477

Gnomad SAS

AF:

0.796

Gnomad FIN

AF:

0.692

Gnomad MID

AF:

0.785

Gnomad NFE

AF:

0.838

Gnomad OTH

AF:

0.811

GnomAD2 exomes

AF:

0.752

AC:

188938

AN:

251182

AF XY:

0.764

show subpopulations

Gnomad AFR exome

AF:

0.864

Gnomad AMR exome

AF:

0.537

Gnomad ASJ exome

AF:

0.838

Gnomad EAS exome

AF:

0.471

Gnomad FIN exome

AF:

0.696

Gnomad NFE exome

AF:

0.836

Gnomad OTH exome

AF:

0.783

GnomAD4 exome

AF:

0.820

AC:

1197202

AN:

1460028

Hom.:

496692

Cov.:

AF XY:

0.820

AC XY:

595777

AN XY:

726472

show subpopulations

African (AFR)

AF:

0.865

AC:

28908

AN:

33438

American (AMR)

AF:

0.559

AC:

24994

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.843

AC:

22021

AN:

26126

East Asian (EAS)

AF:

0.481

AC:

19103

AN:

39690

South Asian (SAS)

AF:

0.799

AC:

68935

AN:

86230

European-Finnish (FIN)

AF:

0.699

AC:

37152

AN:

53186

Middle Eastern (MID)

AF:

0.781

AC:

4475

AN:

5732

European-Non Finnish (NFE)

AF:

0.849

AC:

942815

AN:

1110576

Other (OTH)

AF:

0.809

AC:

48799

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

9692

19385

29077

38770

48462

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.806

AC:

122595

AN:

152118

Hom.:

50083

Cov.:

AF XY:

0.795

AC XY:

59102

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.862

AC:

35792

AN:

41514

American (AMR)

AF:

0.689

AC:

10542

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.849

AC:

2947

AN:

3472

East Asian (EAS)

AF:

0.476

AC:

2451

AN:

5144

South Asian (SAS)

AF:

0.797

AC:

3847

AN:

4824

European-Finnish (FIN)

AF:

0.692

AC:

7314

AN:

10568

Middle Eastern (MID)

AF:

0.776

AC:

228

AN:

294

European-Non Finnish (NFE)

AF:

0.838

AC:

56949

AN:

67992

Other (OTH)

AF:

0.813

AC:

1716

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1173

2346

3518

4691

5864

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.828

Hom.:

99239

Bravo

AF:

0.803

Asia WGS

AF:

0.702

AC:

2443

AN:

3478

EpiCase

AF:

0.844

EpiControl

AF:

0.843

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 26, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Gonadotropin-independent familial sexual precocity

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

7.3

(source)

DANN

Benign

0.78

PhyloP100

0.57

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000066

dbscSNV1_RF

Benign

0.0

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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rs6755901

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