NM_000233.4:c.162-1595C>T

Variant names:

• chr2-48732893-G-A
• rs10495960
• NM_000233.4:c.162-1595C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000233.4(LHCGR):​c.162-1595C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 534,206 control chromosomes in the GnomAD database, including 9,169 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (2177 hom., cov: 32)
  • Exomes 𝑓: 0.17 (6992 hom.)
• Consequence: LHCGR NM_000233.4 intron
• Scores: Splicing: ADA: 0.00005694
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.363
• Publications: 15 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:):

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]

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019029975).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.306 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.162-1595C>T		intron	N/A	NP_000224.2
	STON1-GTF2A1L	NM_001198593.2		c.3442-43387G>A		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.162-1595C>T		intron	N/A	ENSP00000294954.6
	ENSG00000279956	ENST00000602369.3	TSL:5	n.162-1595C>T		intron	N/A	ENSP00000473498.1
	GTF2A1L	ENST00000508440.1	TSL:2	c.277G>A	p.Ala93Thr	missense splice_region	Exon 3 of 3	ENSP00000421474.1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22373 AN: 152024 Hom.: 2171 Cov.: 32

Gnomad AFR AF: 0.0408

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.0608

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.0382

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.146

GnomAD2 exomes AF: 0.185 AC: 45551 AN: 246534 AF XY: 0.174

Gnomad AFR exome AF: 0.0337

Gnomad AMR exome AF: 0.346

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.320

Gnomad FIN exome AF: 0.191

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.170 AC: 64815 AN: 382064 Hom.: 6992 Cov.: 0 AF XY: 0.157 AC XY: 34247 AN XY: 217498

African (AFR) AF: 0.0371 AC: 390 AN: 10506

American (AMR) AF: 0.343 AC: 12435 AN: 36264

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 1504 AN: 11740

East Asian (EAS) AF: 0.312 AC: 4103 AN: 13168

South Asian (SAS) AF: 0.0557 AC: 3718 AN: 66720

European-Finnish (FIN) AF: 0.188 AC: 6058 AN: 32296

Middle Eastern (MID) AF: 0.0547 AC: 156 AN: 2854

European-Non Finnish (NFE) AF: 0.176 AC: 33770 AN: 191818

Other (OTH) AF: 0.161 AC: 2681 AN: 16698

GnomAD4 genome AF: 0.147 AC: 22380 AN: 152142 Hom.: 2177 Cov.: 32 AF XY: 0.149 AC XY: 11054 AN XY: 74362

African (AFR) AF: 0.0407 AC: 1691 AN: 41516

American (AMR) AF: 0.252 AC: 3856 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 406 AN: 3468

East Asian (EAS) AF: 0.318 AC: 1645 AN: 5168

South Asian (SAS) AF: 0.0603 AC: 291 AN: 4828

European-Finnish (FIN) AF: 0.193 AC: 2044 AN: 10586

Middle Eastern (MID) AF: 0.0377 AC: 11 AN: 292

European-Non Finnish (NFE) AF: 0.176 AC: 11973 AN: 67994

Other (OTH) AF: 0.143 AC: 301 AN: 2104

Alfa AF: 0.159 Hom.: 5143

Bravo AF: 0.151

TwinsUK AF: 0.169 AC: 627

ALSPAC AF: 0.187 AC: 720

ESP6500AA AF: 0.0379 AC: 140

ESP6500EA AF: 0.162 AC: 1323

ExAC AF: 0.173 AC: 20930

Asia WGS AF: 0.160 AC: 554 AN: 3478

EpiCase AF: 0.162

EpiControl AF: 0.164

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.8
DANN	Benign	0.63
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.96	T
PhyloP100		0.36
PROVEAN	Benign	0.030	N
REVEL	Benign	0.0050
Sift	Benign	0.033	D
Sift4G	Benign	0.067	T
ClinPred		0.0021	T
GERP RS		0.031
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.0
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: rs10495960; hg19: chr2-48960032; COSMIC: COSV54297584;