rs4597581

Variant names:

• chr2-48731456-A-G
• rs4597581
• NM_000233.4:c.162-158T>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000233.4(LHCGR):​c.162-158T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 152,154 control chromosomes in the GnomAD database, including 2,500 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.16 (2500 hom., cov: 32)
• Consequence: LHCGR NM_000233.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.511

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-48731456-A-G is Benign according to our data. Variant chr2-48731456-A-G is described in ClinVar as [Benign]. Clinvar id is 1245065.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHCGR	NM_000233.4	c.162-158T>C		intron_variant	Intron 1 of 10	ENST00000294954.12	NP_000224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHCGR	ENST00000294954.12	c.162-158T>C		intron_variant	Intron 1 of 10	1	NM_000233.4	ENSP00000294954.6
ENSG00000279956	ENST00000602369.3	n.162-158T>C		intron_variant	Intron 1 of 12	5		ENSP00000473498.1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24495 AN: 152038 Hom.: 2496 Cov.: 32

Gnomad AFR AF: 0.0537

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.0643

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.182

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.161 AC: 24519 AN: 152154 Hom.: 2500 Cov.: 32 AF XY: 0.161 AC XY: 11967 AN XY: 74402

Gnomad4 AFR AF: 0.0539

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.0642

Gnomad4 SAS AF: 0.320

Gnomad4 FIN AF: 0.169

Gnomad4 NFE AF: 0.224

Gnomad4 OTH AF: 0.184

Alfa AF: 0.212 Hom.: 4948

Bravo AF: 0.149

Asia WGS AF: 0.196 AC: 683 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

GeneDx

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	-0.58
CADD	Benign	12
DANN	Benign	0.80

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: rs4597581; hg19: chr2-48958595;