2-48687549-A-G

Position:

chr2-48687549-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000233.4(LHCGR):c.*148T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.067 in 650,988 control chromosomes in the GnomAD database, including 2,316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1172 hom., cov: 32)

Exomes 𝑓: 0.057 ( 1144 hom. )

Consequence

LHCGR
NM_000233.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.197

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:

STON1-GTF2A1L (HGNC:):

STON1-GTF2A1L links:

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]

GTF2A1L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 2-48687549-A-G is Benign according to our data. Variant chr2-48687549-A-G is described in ClinVar as [Benign]. Clinvar id is 336455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-48687549-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHCGR	NM_000233.4 linkuse as main transcript	c.*148T>C		3_prime_UTR_variant	11/11	ENST00000294954.12
STON1-GTF2A1L	NM_001198593.2 linkuse as main transcript	c.3441+15869A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHCGR	ENST00000294954.12 linkuse as main transcript	c.*148T>C		3_prime_UTR_variant	11/11	1	NM_000233.4	A2	P22888-1
GTF2A1L	ENST00000508440.1 linkuse as main transcript	c.276+15869A>G		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.100

AC:

15246

AN:

152144

Hom.:

1167

Cov.:

show subpopulations

Gnomad AFR

AF:

0.213

Gnomad AMI

AF:

0.0548

Gnomad AMR

AF:

0.0578

Gnomad ASJ

AF:

0.0392

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0151

Gnomad FIN

AF:

0.0678

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0645

Gnomad OTH

AF:

0.0808

GnomAD4 exome

AF:

0.0568

AC:

28338

AN:

498726

Hom.:

1144

Cov.:

AF XY:

0.0541

AC XY:

14355

AN XY:

265490

show subpopulations

Gnomad4 AFR exome

AF:

0.211

Gnomad4 AMR exome

AF:

0.0410

Gnomad4 ASJ exome

AF:

0.0440

Gnomad4 EAS exome

AF:

0.000158

Gnomad4 SAS exome

AF:

0.0152

Gnomad4 FIN exome

AF:

0.0647

Gnomad4 NFE exome

AF:

0.0629

Gnomad4 OTH exome

AF:

0.0655

GnomAD4 genome

AF:

0.100

AC:

15260

AN:

152262

Hom.:

1172

Cov.:

AF XY:

0.0956

AC XY:

7119

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.213

Gnomad4 AMR

AF:

0.0576

Gnomad4 ASJ

AF:

0.0392

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0151

Gnomad4 FIN

AF:

0.0678

Gnomad4 NFE

AF:

0.0645

Gnomad4 OTH

AF:

0.0799

Alfa

AF:

0.0783

Hom.:

141

Bravo

AF:

0.106

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2018	- -

Hypergonadotropic hypogonadism

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Leydig cell agenesis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Gonadotropin-independent familial sexual precocity

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.35

DANN

Benign

0.53

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over