rs5030775

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000894.3(LHB):c.52G>A(p.Ala18Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,611,654 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0056 ( 5 hom., cov: 31)

Exomes 𝑓: 0.00066 ( 9 hom. )

Consequence

LHB
NM_000894.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.317

Variant links:

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 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 (MetaRNN=0.0048998).

BP6

Variant 19-49016678-C-T is Benign according to our data. Variant chr19-49016678-C-T is described in ClinVar as [Benign]. Clinvar id is 1224995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0056 (852/152132) while in subpopulation AFR AF= 0.0193 (800/41420). AF 95% confidence interval is 0.0182. There are 5 homozygotes in gnomad4. There are 399 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHB	NM_000894.3 link	c.52G>A	p.Ala18Thr	missense_variant	Exon 2 of 3	ENST00000649238.3	NP_000885.1	P01229A0A0F7RQE6
LHB	XM_047438832.1 link	c.100G>A	p.Ala34Thr	missense_variant	Exon 1 of 2		XP_047294788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHB	ENST00000649238.3 link	c.52G>A	p.Ala18Thr	missense_variant	Exon 2 of 3		NM_000894.3	ENSP00000497294.2		P01229
LHB	ENST00000649284.1 link	n.143G>A		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00560

AC:

851

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00162

AC:

407

AN:

250592

Hom.:

AF XY:

0.00130

AC XY:

176

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.0226

Gnomad AMR exome

AF:

0.000983

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000658

AC:

960

AN:

1459522

Hom.:

Cov.:

142

AF XY:

0.000572

AC XY:

415

AN XY:

726138

show subpopulations

Gnomad4 AFR exome

AF:

0.0218

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000863

Gnomad4 OTH exome

AF:

0.00130

GnomAD4 genome

AF:

0.00560

AC:

852

AN:

152132

Hom.:

Cov.:

AF XY:

0.00536

AC XY:

399

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0193

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00188

Hom.:

ESP6500AA

AF:

0.0207

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00228

AC:

277

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 13, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 11870227) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LHB-related disorder

Benign:1

Oct 31, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

CADD

Benign

3.6

DANN

Benign

0.90

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.36

.;T

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.56

N;.

REVEL

Benign

0.043

Sift

Benign

0.32

T;.

Sift4G

Benign

0.60

T;.

Polyphen

0.0020

B;B

Vest4

0.034

MVP

0.38

MPC

0.075

ClinPred

0.00099

GERP RS

1.3

Varity_R

0.031

gMVP

0.30

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