2-48687169-A-G

Variant names:

• chr2-48687169-A-G
• rs73928203
• NM_000233.4:c.*528T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000233.4(LHCGR):​c.*528T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0382 in 159,004 control chromosomes in the GnomAD database, including 394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (393 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (1 hom.)
• Consequence: LHCGR NM_000233.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.61
• 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=-0.91).
• BP6: Variant 2-48687169-A-G is Benign according to our data. Variant chr2-48687169-A-G is described in ClinVar as Benign. ClinVar VariationId is 336448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

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.*528T>C		3_prime_UTR	Exon 11 of 11	NP_000224.2	P22888-1
	STON1-GTF2A1L	NM_001198593.2		c.3441+15489A>G		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.*528T>C		3_prime_UTR	Exon 11 of 11	ENSP00000294954.6	P22888-1
	ENSG00000279956	ENST00000602369.3	TSL:5	n.*220+7055T>C		intron	N/A	ENSP00000473498.1	R4GN57
	LHCGR	ENST00000913067.1		c.*528T>C		3_prime_UTR	Exon 7 of 7	ENSP00000583126.1

Frequencies

GnomAD3 genomes AF: 0.0397 AC: 6044 AN: 152156 Hom.: 393 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0325

GnomAD4 exome AF: 0.00163 AC: 11 AN: 6730 Hom.: 1 Cov.: 0 AF XY: 0.00133 AC XY: 5 AN XY: 3764

African (AFR) AF: 0.200 AC: 6 AN: 30

American (AMR) AF: 0.00318 AC: 4 AN: 1256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 38

East Asian (EAS) AF: 0.00 AC: 0 AN: 270

South Asian (SAS) AF: 0.00 AC: 0 AN: 654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 66

Middle Eastern (MID) AF: 0.125 AC: 1 AN: 8

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4168

Other (OTH) AF: 0.00 AC: 0 AN: 240

GnomAD4 genome AF: 0.0398 AC: 6057 AN: 152274 Hom.: 393 Cov.: 32 AF XY: 0.0377 AC XY: 2810 AN XY: 74462

African (AFR) AF: 0.139 AC: 5759 AN: 41524

American (AMR) AF: 0.0124 AC: 189 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68020

Other (OTH) AF: 0.0321 AC: 68 AN: 2116

Alfa AF: 0.00682 Hom.: 2

Bravo AF: 0.0445

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.91
CADD	Benign	0.036
DANN	Benign	0.32
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs73928203; hg19: chr2-48914308;