19-49016130-C-T

Position:

chr19-49016130-C-T

Variant summary

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

The NM_000894.3(LHB):c.364G>A(p.Gly122Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,612,864 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 2 hom. )

Consequence

LHB
NM_000894.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:2

Conservation

PhyloP100: 0.697

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=0.045683086).

BP6

Variant 19-49016130-C-T is Benign according to our data. Variant chr19-49016130-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 14415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000348 (53/152278) while in subpopulation EAS AF= 0.00927 (48/5176). AF 95% confidence interval is 0.00719. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHB	NM_000894.3 linkuse as main transcript	c.364G>A	p.Gly122Ser	missense_variant	3/3	ENST00000649238.3	NP_000885.1
LHB	XM_047438832.1 linkuse as main transcript	c.412G>A	p.Gly138Ser	missense_variant	2/2		XP_047294788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHB	ENST00000649238.3 linkuse as main transcript	c.364G>A	p.Gly122Ser	missense_variant	3/3		NM_000894.3	ENSP00000497294	P1
LHB	ENST00000649284.1 linkuse as main transcript	n.455G>A		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00906

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000629

AC:

158

AN:

251350

Hom.:

AF XY:

0.000581

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00848

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000201

AC:

294

AN:

1460586

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

146

AN XY:

726618

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00703

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000348

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00927

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.000336

ExAC

AF:

0.000659

AC:

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Variant of unknown significance

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Mar 01, 2003

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

Isolated lutropin deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 19, 2020

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as likely benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Hypogonadotropic hypogonadism 23 with or without anosmia (MIM #228300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of Kallmann syndrome. The gnomAD frequency data is skewed towards the East Asian population, with 171 out of 174 heterozygous and 1 homozygote, being observed in this subpopulation. (SB) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated cystine-knot domain (RCSB-PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has one likely benign and one VUS entry in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. A competitive binding inhibition assay indicates that this variant causes lower receptor binding ability at high concentrations. Additionally, progesterone production was lower compared to wild-type (PMID: 12189497). 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.41

T;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.81

.;T

M_CAP

Benign

0.071

MetaRNN

Benign

0.046

T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

0.86

L;L

MutationTaster

Benign

0.087

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.010

N;.

REVEL

Benign

0.25

Sift

Benign

0.42

T;.

Sift4G

Benign

0.42

T;.

Polyphen

1.0

D;D

Vest4

0.19

MVP

0.91

MPC

0.11

ClinPred

0.10

GERP RS

2.6

Varity_R

0.052

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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