rs147247585

Variant names:

• chr19-49016254-A-G
• rs147247585
• NM_000894.3:c.240T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS1

The NM_000894.3(LHB):​c.240T>C​(p.Arg80Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,612,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: LHB NM_000894.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -5.36
• Publications: 1 publications found

Genes affected

LHB (HGNC:6584): (luteinizing hormone subunit beta) This gene is a member of the glycoprotein hormone beta chain family and encodes the beta subunit of luteinizing hormone (LH). Glycoprotein hormones are heterodimers consisting of a common alpha subunit and an unique beta subunit which confers biological specificity. LH is expressed in the pituitary gland and promotes spermatogenesis and ovulation by stimulating the testes and ovaries to synthesize steroids. The genes for the beta chains of chorionic gonadotropin and for luteinizing hormone are contiguous on chromosome 19q13.3. Mutations in this gene are associated with hypogonadism which is characterized by infertility and pseudohermaphroditism. [provided by RefSeq, Jul 2008]

LHB Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism 23 with or without anosmia

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 19-49016254-A-G is Benign according to our data. Variant chr19-49016254-A-G is described in ClinVar as Benign. ClinVar VariationId is 2712219.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-5.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000689 (105/152318) while in subpopulation EAS AF = 0.00213 (11/5170). AF 95% confidence interval is 0.00119. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000894.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHB	NM_000894.3	MANE Select	c.240T>C	p.Arg80Arg	synonymous	Exon 3 of 3	NP_000885.1	P01229

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHB	ENST00000649238.3	MANE Select	c.240T>C	p.Arg80Arg	synonymous	Exon 3 of 3	ENSP00000497294.2	P01229
	LHB	ENST00000649284.1		n.331T>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.000696 AC: 106 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000535 AC: 134 AN: 250664 AF XY: 0.000531

Gnomad AFR exome AF: 0.00118

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00447

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000253 AC: 370 AN: 1460086 Hom.: 0 Cov.: 64 AF XY: 0.000240 AC XY: 174 AN XY: 726386

African (AFR) AF: 0.00114 AC: 38 AN: 33440

American (AMR) AF: 0.000492 AC: 22 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00207 AC: 82 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.000219 AC: 1 AN: 4556

European-Non Finnish (NFE) AF: 0.000180 AC: 200 AN: 1111854

Other (OTH) AF: 0.000382 AC: 23 AN: 60250

GnomAD4 genome AF: 0.000689 AC: 105 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74472

African (AFR) AF: 0.00125 AC: 52 AN: 41584

American (AMR) AF: 0.00157 AC: 24 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00213 AC: 11 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68016

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.000880

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	LHB-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0020
DANN	Benign	0.38
PhyloP100		-5.4
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs147247585; hg19: chr19-49519511;