rs12470652

chr2-48694299-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.13

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]

STON1-GTF2A1L (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity LSHR_HUMAN
• 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	UniProt
LHCGR	NM_000233.4	c.872A>G	p.Asn291Ser	missense_variant	10/11	ENST00000294954.12
STON1-GTF2A1L	NM_001198593.2	c.3441+22619T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHCGR	ENST00000294954.12	c.872A>G	p.Asn291Ser	missense_variant	10/11	1	NM_000233.4	A2

Frequencies

GnomAD3 genomes AF: 0.0375 AC: 5707 AN: 152168 Hom.: 139 Cov.: 33

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

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.: 28 AF XY: 0.0481 AC XY: 34435 AN XY: 715502

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.: 33 AF XY: 0.0364 AC XY: 2711 AN XY: 74458

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: 75

ESP6500EA AF: 0.0546 AC: 469

ExAC AF: 0.0365 AC: 4422

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

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	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	22
Dann	Benign	0.94
DEOGEN2	Benign	0.086	T;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	T;T;T
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Uncertain	0.026	D
MutationAssessor	Benign	1.3	L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.57	T
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	T
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

Other links and lift over

dbSNP: rs12470652; hg19: chr2-48921438; COSMIC: COSV54299337;