chr2-48755625-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_000233.4(LHCGR):c.47T>A(p.Leu16Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,128,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000079 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

LHCGR
NM_000233.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83

Publications

19 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]

LHCGR links:

ENSG00000279956 (HGNC:):

ENSG00000279956 links:

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]

STON1-GTF2A1L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHCGR	NM_000233.4 link	c.47T>A	p.Leu16Gln	missense_variant	Exon 1 of 11	ENST00000294954.12	NP_000224.2	P22888-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHCGR	ENST00000294954.12 link	c.47T>A	p.Leu16Gln	missense_variant	Exon 1 of 11	1	NM_000233.4	ENSP00000294954.6		P22888-1
ENSG00000279956	ENST00000602369.3 link	n.47T>A		non_coding_transcript_exon_variant	Exon 1 of 13	5		ENSP00000473498.1		R4GN57

Frequencies

GnomAD3 genomes

AF:

0.00000788

AC:

AN:

126850

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000183

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000106

AC:

AN:

132688

AF XY:

0.0000550

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000445

Gnomad NFE exome

AF:

0.000218

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000569

AC:

AN:

1002004

Hom.:

Cov.:

AF XY:

0.0000418

AC XY:

AN XY:

502514

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25706

American (AMR)

AF:

0.00

AC:

AN:

32746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18940

East Asian (EAS)

AF:

0.00

AC:

AN:

35518

South Asian (SAS)

AF:

0.0000274

AC:

AN:

73068

European-Finnish (FIN)

AF:

0.000123

AC:

AN:

32500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2982

European-Non Finnish (NFE)

AF:

0.0000693

AC:

AN:

736288

Other (OTH)

AF:

0.00

AC:

AN:

44256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

AF:

0.00000788

AC:

AN:

126850

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

62184

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

35466

American (AMR)

AF:

0.00

AC:

AN:

13048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2726

East Asian (EAS)

AF:

0.00

AC:

AN:

5126

South Asian (SAS)

AF:

0.00

AC:

AN:

4354

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8976

Middle Eastern (MID)

AF:

0.00

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.0000183

AC:

AN:

54596

Other (OTH)

AF:

0.00

AC:

AN:

1684

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00297

Hom.:

ExAC

AF:

0.000512

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

See cases

Uncertain:1

Dec 21, 2021

Institute of Human Genetics, University Hospital Muenster

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG categories: PM2,PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.37

T;.;.;.

Eigen

Benign

-0.00066

Eigen_PC

Benign

-0.049

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.41

T;T;T;T

M_CAP

Pathogenic

0.90

MetaRNN

Uncertain

0.43

T;T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Benign

0.81

L;.;.;.

PhyloP100

1.8

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Uncertain

0.45

Sift

Uncertain

0.010

D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D

Polyphen

0.97

D;.;.;.

Vest4

0.37

MVP

0.98

MPC

0.088

ClinPred

0.15

GERP RS

4.2

PromoterAI

-0.055

Neutral

(source)

Varity_R

0.33

gMVP

0.57

Mutation Taster

=78/22

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over