NM_000233.4:c.935A>G

Variant names:

• chr2-48694236-T-C
• rs2293275
• NM_000233.4:c.935A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP2 BP6_Very_Strong BA1

The NM_000233.4(LHCGR):​c.935A>G​(p.Asn312Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.582 in 1,565,618 control chromosomes in the GnomAD database, including 273,076 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (22631 hom., cov: 33)
  • Exomes 𝑓: 0.59 (250445 hom.)
• Consequence: LHCGR NM_000233.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.19
• Publications: 102 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 -15 ACMG points.

• 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.
• BP6: Variant 2-48694236-T-C is Benign according to our data. Variant chr2-48694236-T-C is described in ClinVar as Benign. ClinVar VariationId is 255609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.91 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHCGR	NM_000233.4	MANE Select	c.935A>G	p.Asn312Ser	missense	Exon 10 of 11	NP_000224.2
	STON1-GTF2A1L	NM_001198593.2		c.3441+22556T>C		intron	N/A	NP_001185522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHCGR	ENST00000294954.12	TSL:1 MANE Select	c.935A>G	p.Asn312Ser	missense	Exon 10 of 11	ENSP00000294954.6
	ENSG00000279956	ENST00000602369.3	TSL:5	n.*208A>G		non_coding_transcript_exon	Exon 9 of 13	ENSP00000473498.1
	ENSG00000279956	ENST00000602369.3	TSL:5	n.*208A>G		3_prime_UTR	Exon 9 of 13	ENSP00000473498.1

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79577 AN: 151958 Hom.: 22629 Cov.: 33

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.635

Gnomad ASJ AF: 0.644

Gnomad EAS AF: 0.932

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.580

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.581

Gnomad OTH AF: 0.568

GnomAD2 exomes AF: 0.613 AC: 143913 AN: 234642 AF XY: 0.613

Gnomad AFR exome AF: 0.287

Gnomad AMR exome AF: 0.707

Gnomad ASJ exome AF: 0.670

Gnomad EAS exome AF: 0.930

Gnomad FIN exome AF: 0.572

Gnomad NFE exome AF: 0.582

Gnomad OTH exome AF: 0.621

GnomAD4 exome AF: 0.589 AC: 832319 AN: 1413542 Hom.: 250445 Cov.: 27 AF XY: 0.590 AC XY: 415494 AN XY: 704166

African (AFR) AF: 0.291 AC: 9562 AN: 32860

American (AMR) AF: 0.697 AC: 30156 AN: 43272

Ashkenazi Jewish (ASJ) AF: 0.663 AC: 17076 AN: 25738

East Asian (EAS) AF: 0.937 AC: 36769 AN: 39254

South Asian (SAS) AF: 0.612 AC: 51273 AN: 83764

European-Finnish (FIN) AF: 0.573 AC: 30216 AN: 52736

Middle Eastern (MID) AF: 0.696 AC: 3957 AN: 5686

European-Non Finnish (NFE) AF: 0.577 AC: 617927 AN: 1071566

Other (OTH) AF: 0.603 AC: 35383 AN: 58666

GnomAD4 genome AF: 0.523 AC: 79610 AN: 152076 Hom.: 22631 Cov.: 33 AF XY: 0.531 AC XY: 39499 AN XY: 74346

African (AFR) AF: 0.298 AC: 12384 AN: 41502

American (AMR) AF: 0.635 AC: 9709 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.644 AC: 2234 AN: 3468

East Asian (EAS) AF: 0.932 AC: 4826 AN: 5176

South Asian (SAS) AF: 0.620 AC: 2991 AN: 4824

European-Finnish (FIN) AF: 0.580 AC: 6142 AN: 10586

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.581 AC: 39490 AN: 67920

Other (OTH) AF: 0.568 AC: 1198 AN: 2110

Alfa AF: 0.578 Hom.: 115010

Bravo AF: 0.522

TwinsUK AF: 0.575 AC: 2131

ALSPAC AF: 0.590 AC: 2272

ESP6500AA AF: 0.297 AC: 1307

ESP6500EA AF: 0.591 AC: 5074

ExAC AF: 0.592 AC: 71626

Asia WGS AF: 0.707 AC: 2459 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Gonadotropin-independent familial sexual precocity (1)
-	-	1	Hypergonadotropic hypogonadism (1)
-	-	1	Leydig cell agenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	9.4e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.73	N
PhyloP100		1.2
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.12
Sift	Benign	0.72	T
Sift4G	Benign	0.77	T
Polyphen		0.0040	B
Vest4		0.067
MPC		0.068
ClinPred		0.0051	T
GERP RS		3.9
Varity_R		0.043
gMVP		0.41
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.35		Position offset: -12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2293275; hg19: chr2-48921375; COSMIC: COSV54295902;