rs1800447

Variant names:

• chr19-49016648-A-G
• rs1800447
• NM_000894.3:c.82T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000894.3(LHB):​c.82T>C​(p.Trp28Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0756 in 1,608,732 control chromosomes in the GnomAD database, including 5,114 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (484 hom., cov: 31)
  • Exomes 𝑓: 0.076 (4630 hom.)
• Consequence: LHB NM_000894.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.604
• Publications: 27 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005592197).
• BP6: Variant 19-49016648-A-G is Benign according to our data. Variant chr19-49016648-A-G is described in ClinVar as Benign. ClinVar VariationId is 446195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0812 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHB	NM_000894.3	MANE Select	c.82T>C	p.Trp28Arg	missense	Exon 2 of 3	NP_000885.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHB	ENST00000649238.3	MANE Select	c.82T>C	p.Trp28Arg	missense	Exon 2 of 3	ENSP00000497294.2
	LHB	ENST00000649284.1		n.173T>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0754 AC: 11386 AN: 150980 Hom.: 481 Cov.: 31

Gnomad AFR AF: 0.0583

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0677

Gnomad ASJ AF: 0.0652

Gnomad EAS AF: 0.0528

Gnomad SAS AF: 0.0259

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0831

Gnomad OTH AF: 0.0816

GnomAD2 exomes AF: 0.0648 AC: 15994 AN: 246848 AF XY: 0.0642

Gnomad AFR exome AF: 0.0509

Gnomad AMR exome AF: 0.0413

Gnomad ASJ exome AF: 0.0551

Gnomad EAS exome AF: 0.0585

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.0783

Gnomad OTH exome AF: 0.0740

GnomAD4 exome AF: 0.0757 AC: 110271 AN: 1457636 Hom.: 4630 Cov.: 135 AF XY: 0.0750 AC XY: 54362 AN XY: 725230

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

African (AFR) AF: 0.0584 AC: 1920 AN: 32884

American (AMR) AF: 0.0449 AC: 2005 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.0605 AC: 1579 AN: 26112

East Asian (EAS) AF: 0.0564 AC: 2238 AN: 39688

South Asian (SAS) AF: 0.0280 AC: 2409 AN: 86164

European-Finnish (FIN) AF: 0.131 AC: 6797 AN: 51960

Middle Eastern (MID) AF: 0.0812 AC: 380 AN: 4682

European-Non Finnish (NFE) AF: 0.0795 AC: 88403 AN: 1111302

Other (OTH) AF: 0.0754 AC: 4540 AN: 60190

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0755 AC: 11406 AN: 151096 Hom.: 484 Cov.: 31 AF XY: 0.0753 AC XY: 5557 AN XY: 73796

African (AFR) AF: 0.0586 AC: 2395 AN: 40880

American (AMR) AF: 0.0675 AC: 1029 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.0652 AC: 226 AN: 3466

East Asian (EAS) AF: 0.0533 AC: 274 AN: 5144

South Asian (SAS) AF: 0.0257 AC: 124 AN: 4816

European-Finnish (FIN) AF: 0.135 AC: 1419 AN: 10494

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0831 AC: 5628 AN: 67760

Other (OTH) AF: 0.0831 AC: 174 AN: 2094

Alfa AF: 0.0703 Hom.: 143

Bravo AF: 0.0726

TwinsUK AF: 0.0636 AC: 236

ALSPAC AF: 0.0734 AC: 283

ESP6500AA AF: 0.0431 AC: 190

ESP6500EA AF: 0.0747 AC: 642

ExAC AF: 0.0705 AC: 8558

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 7586598, 25111116, 19890021, 7714098, 22108961, 23725475, 7904610)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.0
DANN	Benign	0.56
DEOGEN2	Benign	0.38	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0038	N
LIST_S2	Benign	0.061	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.60
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.17
Sift	Benign	0.39	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.010
MutPred		0.16		Gain of disorder (P = 0.0104)
MPC		0.13
ClinPred		0.0012	T
GERP RS		0.27
PromoterAI		-0.041	Neutral
Varity_R		0.066
gMVP		0.67
Mutation Taster		=99/1	polymorphism (auto)

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: rs1800447; hg19: chr19-49519905; COSMIC: COSV55485237; COSMIC: COSV55485237;