2-48729373-A-G

Variant names:

• chr2-48729373-A-G
• rs11897846
• NM_000233.4:c.234-146T>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.234-146T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 703,872 control chromosomes in the GnomAD database, including 41,053 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11559 hom., cov: 32)
  • Exomes 𝑓: 0.31 (29494 hom.)
• Consequence: LHCGR NM_000233.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.49
• Publications: 5 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=-0.7).
• BP6: Variant 2-48729373-A-G is Benign according to our data. Variant chr2-48729373-A-G is described in ClinVar as Benign. ClinVar VariationId is 1272187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.583 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.234-146T>C		intron	N/A	NP_000224.2	P22888-1
	STON1-GTF2A1L	NM_001198593.2		c.3442-46907A>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.234-146T>C		intron	N/A	ENSP00000294954.6	P22888-1
	ENSG00000279956	ENST00000602369.3	TSL:5	n.233+1854T>C		intron	N/A	ENSP00000473498.1	R4GN57
	STON1-GTF2A1L	ENST00000402114.6	TSL:2	c.3442-46907A>G		intron	N/A	ENSP00000385701.1

Frequencies

GnomAD3 genomes AF: 0.369 AC: 56028 AN: 151906 Hom.: 11545 Cov.: 32

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.600

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.334

GnomAD4 exome AF: 0.306 AC: 168853 AN: 551848 Hom.: 29494 AF XY: 0.298 AC XY: 88940 AN XY: 298604

African (AFR) AF: 0.518 AC: 7997 AN: 15432

American (AMR) AF: 0.564 AC: 19108 AN: 33886

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 4291 AN: 18664

East Asian (EAS) AF: 0.539 AC: 17214 AN: 31962

South Asian (SAS) AF: 0.240 AC: 14565 AN: 60748

European-Finnish (FIN) AF: 0.346 AC: 11592 AN: 33548

Middle Eastern (MID) AF: 0.192 AC: 720 AN: 3750

European-Non Finnish (NFE) AF: 0.260 AC: 84075 AN: 323664

Other (OTH) AF: 0.308 AC: 9291 AN: 30194

GnomAD4 genome AF: 0.369 AC: 56075 AN: 152024 Hom.: 11559 Cov.: 32 AF XY: 0.375 AC XY: 27844 AN XY: 74324

African (AFR) AF: 0.505 AC: 20936 AN: 41444

American (AMR) AF: 0.468 AC: 7157 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 747 AN: 3468

East Asian (EAS) AF: 0.600 AC: 3098 AN: 5160

South Asian (SAS) AF: 0.268 AC: 1292 AN: 4818

European-Finnish (FIN) AF: 0.349 AC: 3690 AN: 10578

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 18023 AN: 67962

Other (OTH) AF: 0.334 AC: 705 AN: 2112

Alfa AF: 0.295 Hom.: 23216

Bravo AF: 0.391

Asia WGS AF: 0.410 AC: 1423 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.33
DANN	Benign	0.81
PhyloP100		-1.5
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: rs11897846; hg19: chr2-48956512;