rs4490239

chr2-48721663-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000233.4(LHCGR):c.536+1793A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 470,170 control chromosomes in the GnomAD database, including 7,585 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (1774 hom., cov: 32)
  • Exomes 𝑓: 0.18 (5811 hom.)
• Consequence: LHCGR NM_000233.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.448

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHCGR	NM_000233.4	c.536+1793A>G		intron_variant		ENST00000294954.12
STON1-GTF2A1L	NM_001198593.2	c.3441+49983T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHCGR	ENST00000294954.12	c.536+1793A>G		intron_variant		1	NM_000233.4	A2

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21122 AN: 152146 Hom.: 1767 Cov.: 32

Gnomad AFR AF: 0.0547

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0968

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.159

GnomAD3 exomes AF: 0.168 AC: 24915 AN: 148364 Hom.: 2306 AF XY: 0.177 AC XY: 14163 AN XY: 79920

Gnomad AFR exome AF: 0.0463

Gnomad AMR exome AF: 0.135

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.0859

Gnomad SAS exome AF: 0.254

Gnomad FIN exome AF: 0.175

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.182 AC: 57793 AN: 317906 Hom.: 5811 Cov.: 0 AF XY: 0.190 AC XY: 34090 AN XY: 179722

Gnomad4 AFR exome AF: 0.0488

Gnomad4 AMR exome AF: 0.136

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.0863

Gnomad4 SAS exome AF: 0.250

Gnomad4 FIN exome AF: 0.173

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.174

GnomAD4 genome AF: 0.139 AC: 21142 AN: 152264 Hom.: 1774 Cov.: 32 AF XY: 0.140 AC XY: 10423 AN XY: 74444

Gnomad4 AFR AF: 0.0547

Gnomad4 AMR AF: 0.141

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.0967

Gnomad4 SAS AF: 0.268

Gnomad4 FIN AF: 0.173

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.163

Alfa AF: 0.172 Hom.: 4846

Bravo AF: 0.128

Asia WGS AF: 0.212 AC: 733 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	12
Dann	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4490239; hg19: chr2-48948802;