rs4490239

Variant names:

• chr2-48721663-T-C
• rs4490239
• NM_000233.4:c.536+1793A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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]

ENSG00000279956 (HGNC:):

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]

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
LHCGR	NM_000233.4	c.536+1793A>G		intron_variant	Intron 6 of 10	ENST00000294954.12	NP_000224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHCGR	ENST00000294954.12	c.536+1793A>G		intron_variant	Intron 6 of 10	1	NM_000233.4	ENSP00000294954.6
ENSG00000279956	ENST00000602369.3	n.461+1793A>G		intron_variant	Intron 5 of 12	5		ENSP00000473498.1

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

GnomAD2 exomes AF: 0.168 AC: 24915 AN: 148364 AF XY: 0.177

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 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

African (AFR) AF: 0.0488 AC: 415 AN: 8500

American (AMR) AF: 0.136 AC: 3677 AN: 27128

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 1587 AN: 10776

East Asian (EAS) AF: 0.0863 AC: 795 AN: 9214

South Asian (SAS) AF: 0.250 AC: 14895 AN: 59626

European-Finnish (FIN) AF: 0.173 AC: 4632 AN: 26840

Middle Eastern (MID) AF: 0.146 AC: 399 AN: 2738

European-Non Finnish (NFE) AF: 0.182 AC: 28911 AN: 158822

Other (OTH) AF: 0.174 AC: 2482 AN: 14262

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

African (AFR) AF: 0.0547 AC: 2272 AN: 41564

American (AMR) AF: 0.141 AC: 2157 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 488 AN: 3470

East Asian (EAS) AF: 0.0967 AC: 501 AN: 5182

South Asian (SAS) AF: 0.268 AC: 1289 AN: 4816

European-Finnish (FIN) AF: 0.173 AC: 1832 AN: 10594

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12084 AN: 68022

Other (OTH) AF: 0.163 AC: 345 AN: 2116

Alfa AF: 0.165 Hom.: 7024

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
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4490239; hg19: chr2-48948802; COSMIC: COSV107323880;