NM_000233.4:c.391T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_000233.4(LHCGR):​c.391T>C​(p.Cys131Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LHCGR
NM_000233.4 missense

Scores

5
9
5

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.50

Publications

11 publications found
Variant links:
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]
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.942
PP5
Variant 2-48723689-A-G is Pathogenic according to our data. Variant chr2-48723689-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 14396.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LHCGRNM_000233.4 linkc.391T>C p.Cys131Arg missense_variant Exon 5 of 11 ENST00000294954.12 NP_000224.2 P22888-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LHCGRENST00000294954.12 linkc.391T>C p.Cys131Arg missense_variant Exon 5 of 11 1 NM_000233.4 ENSP00000294954.6 P22888-1
ENSG00000279956ENST00000602369.3 linkn.316T>C non_coding_transcript_exon_variant Exon 4 of 13 5 ENSP00000473498.1 R4GN57

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460464
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
726652
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33438
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26124
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39664
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86234
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1110760
Other (OTH)
AF:
0.00
AC:
0
AN:
60340
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Leydig cell hypoplasia, type II Pathogenic:1
Jul 01, 1997
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.79
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.27
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.72
D;.;.;.;.
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.81
T;D;T;T;D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D
MetaSVM
Uncertain
0.12
D
MutationAssessor
Benign
0.84
L;.;.;.;.
PhyloP100
4.5
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-2.8
D;D;D;D;D
REVEL
Pathogenic
0.83
Sift
Benign
0.35
T;T;D;D;D
Sift4G
Benign
0.35
T;T;D;D;D
Polyphen
1.0
D;.;.;.;.
Vest4
0.83
MutPred
0.89
Gain of MoRF binding (P = 0.0155);Gain of MoRF binding (P = 0.0155);Gain of MoRF binding (P = 0.0155);Gain of MoRF binding (P = 0.0155);.;
MVP
0.95
MPC
0.42
ClinPred
0.97
D
GERP RS
5.9
Varity_R
0.71
gMVP
0.81
Mutation Taster
=2/98
disease causing (ClinVar)

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

Publications

Other links and lift over

dbSNP: rs121912527; hg19: chr2-48950828; API