chr2-48687162-C-T

Position:

• chr2-48687162-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_000233.4(LHCGR):​c.*535G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 158,438 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (0 hom.)
• Consequence: LHCGR NM_000233.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.129

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:):

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

Verdict is Benign. Variant got -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 2-48687162-C-T is Benign according to our data. Variant chr2-48687162-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 336447.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0019 (289/152320) while in subpopulation NFE AF= 0.00282 (192/68026). AF 95% confidence interval is 0.0025. There are 1 homozygotes in gnomad4. There are 138 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHCGR	NM_000233.4	c.*535G>A		3_prime_UTR_variant	11/11	ENST00000294954.12	NP_000224.2
STON1-GTF2A1L	NM_001198593.2	c.3441+15482C>T		intron_variant			NP_001185522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHCGR	ENST00000294954.12	c.*535G>A		3_prime_UTR_variant	11/11	1	NM_000233.4	ENSP00000294954	A2
GTF2A1L	ENST00000508440.1	c.276+15482C>T		intron_variant		2		ENSP00000421474

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152202 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00282

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00229 AC: 14 AN: 6118 Hom.: 0 Cov.: 0 AF XY: 0.00175 AC XY: 6 AN XY: 3438

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00257

Gnomad4 ASJ exome AF: 0.0278

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00170

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00212

Gnomad4 OTH exome AF: 0.00463

GnomAD4 genome AF: 0.00190 AC: 289 AN: 152320 Hom.: 1 Cov.: 32 AF XY: 0.00185 AC XY: 138 AN XY: 74468

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00282

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00238 Hom.: 0

Bravo AF: 0.00212

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Hypergonadotropic hypogonadism Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Leydig cell agenesis Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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	-0.97
CADD	Benign	1.2
DANN	Benign	0.74

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

Other links and lift over

dbSNP: rs534109670; hg19: chr2-48914301;