chr2-48725689-G-C

Variant names:

• chr2-48725689-G-C
• rs773279269
• NM_000233.4:c.370C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000233.4(LHCGR):​c.370C>G​(p.Arg124Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,156 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R124Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LHCGR NM_000233.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.73
• Publications: 2 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.16259 (below the threshold of 3.09). Trascript score misZ: -0.035144 (below the threshold of 3.09). GenCC associations: The gene is linked to Leydig cell hypoplasia, type 1, familial male-limited precocious puberty.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHCGR	NM_000233.4	c.370C>G	p.Arg124Gly	missense_variant	Exon 4 of 11	ENST00000294954.12	NP_000224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHCGR	ENST00000294954.12	c.370C>G	p.Arg124Gly	missense_variant	Exon 4 of 11	1	NM_000233.4	ENSP00000294954.6
ENSG00000279956	ENST00000602369.3	n.295C>G		non_coding_transcript_exon_variant	Exon 3 of 13	5		ENSP00000473498.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460156 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726546

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110612

Other (OTH) AF: 0.00 AC: 0 AN: 60322

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.83	T;T;D;D;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.69	D;D;D;D;D
MetaSVM	Uncertain	0.017	D
MutationAssessor	Benign	0.78	N;.;.;.;.
PhyloP100		3.7
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.2	N;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.14	T;T;T;T;T
Sift4G	Benign	0.090	T;T;D;D;D
Polyphen		0.77	P;.;.;.;.
Vest4		0.71
MutPred		0.55		Loss of MoRF binding (P = 0.0766);Loss of MoRF binding (P = 0.0766);Loss of MoRF binding (P = 0.0766);Loss of MoRF binding (P = 0.0766);.;
MVP		0.90
MPC		0.19
ClinPred		0.90	D
GERP RS		5.2
Varity_R		0.26
gMVP		0.53
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs773279269; hg19: chr2-48952828; COSMIC: COSV54296553; COSMIC: COSV54296553;