NM_000233.4:c.*131C>T

Variant names:

• chr2-48687566-G-A
• rs73928204
• NM_000233.4:c.*131C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000233.4(LHCGR):​c.*131C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 715,800 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (22 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (8 hom.)
• Consequence: LHCGR NM_000233.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.325
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-48687566-G-A is Benign according to our data. Variant chr2-48687566-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 336456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00706 (1074/152192) while in subpopulation AFR AF = 0.0241 (1002/41532). AF 95% confidence interval is 0.0229. There are 22 homozygotes in GnomAd4. There are 535 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000233.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHCGR	NM_000233.4	MANE Select	c.*131C>T		3_prime_UTR	Exon 11 of 11	NP_000224.2	P22888-1
	STON1-GTF2A1L	NM_001198593.2		c.3441+15886G>A		intron	N/A	NP_001185522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHCGR	ENST00000294954.12	TSL:1 MANE Select	c.*131C>T		3_prime_UTR	Exon 11 of 11	ENSP00000294954.6	P22888-1
	ENSG00000279956	ENST00000602369.3	TSL:5	n.*220+6658C>T		intron	N/A	ENSP00000473498.1	R4GN57
	LHCGR	ENST00000913067.1		c.*131C>T		3_prime_UTR	Exon 7 of 7	ENSP00000583126.1

Frequencies

GnomAD3 genomes AF: 0.00704 AC: 1070 AN: 152074 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.000947 AC: 534 AN: 563608 Hom.: 8 Cov.: 7 AF XY: 0.000796 AC XY: 239 AN XY: 300364

African (AFR) AF: 0.0257 AC: 388 AN: 15078

American (AMR) AF: 0.00205 AC: 59 AN: 28756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16852

East Asian (EAS) AF: 0.00 AC: 0 AN: 32252

South Asian (SAS) AF: 0.000166 AC: 9 AN: 54076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33980

Middle Eastern (MID) AF: 0.00130 AC: 3 AN: 2306

European-Non Finnish (NFE) AF: 0.0000257 AC: 9 AN: 349964

Other (OTH) AF: 0.00218 AC: 66 AN: 30344

GnomAD4 genome AF: 0.00706 AC: 1074 AN: 152192 Hom.: 22 Cov.: 32 AF XY: 0.00719 AC XY: 535 AN XY: 74406

African (AFR) AF: 0.0241 AC: 1002 AN: 41532

American (AMR) AF: 0.00366 AC: 56 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68006

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00300 Hom.: 1

Bravo AF: 0.00798

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Gonadotropin-independent familial sexual precocity (1)
-	-	1	Hypergonadotropic hypogonadism (1)
-	-	1	Leydig cell agenesis (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.16
DANN	Benign	0.51
PhyloP100		-0.33
Mutation Taster		=100/0	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: rs73928204; hg19: chr2-48914705;