rs4002462

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000894.3(LHB):c.16-26T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.568 in 1,532,984 control chromosomes in the GnomAD database, including 254,672 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 29273 hom., cov: 29)

Exomes 𝑓: 0.56 ( 225399 hom. )

Consequence

LHB
NM_000894.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.521

Publications

7 publications found

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 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

LHB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.118).

BP6

Variant 19-49016740-A-G is Benign according to our data. Variant chr19-49016740-A-G is described in ClinVar as Benign. ClinVar VariationId is 518304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHB	NM_000894.3 link	c.16-26T>C		intron_variant	Intron 1 of 2	ENST00000649238.3	NP_000885.1	P01229A0A0F7RQE6
LHB	XM_047438832.1 link	c.38T>C	p.Leu13Pro	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.16-26T>C		intron_variant	Intron 1 of 2		NM_000894.3	ENSP00000497294.2		P01229
LHB	ENST00000649284.1 link	n.81T>C		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.617

AC:

92732

AN:

150292

Hom.:

29242

Cov.:

show subpopulations

Gnomad AFR

AF:

0.717

Gnomad AMI

AF:

0.655

Gnomad AMR

AF:

0.665

Gnomad ASJ

AF:

0.559

Gnomad EAS

AF:

0.326

Gnomad SAS

AF:

0.528

Gnomad FIN

AF:

0.576

Gnomad MID

AF:

0.668

Gnomad NFE

AF:

0.583

Gnomad OTH

AF:

0.590

GnomAD2 exomes

AF:

0.573

AC:

131038

AN:

228628

AF XY:

0.565

show subpopulations

Gnomad AFR exome

AF:

0.722

Gnomad AMR exome

AF:

0.698

Gnomad ASJ exome

AF:

0.555

Gnomad EAS exome

AF:

0.315

Gnomad FIN exome

AF:

0.560

Gnomad NFE exome

AF:

0.573

Gnomad OTH exome

AF:

0.571

GnomAD4 exome

AF:

0.563

AC:

778687

AN:

1382572

Hom.:

225399

Cov.:

AF XY:

0.562

AC XY:

385011

AN XY:

685618

show subpopulations

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

African (AFR)

AF:

0.738

AC:

23787

AN:

32228

American (AMR)

AF:

0.700

AC:

28560

AN:

40828

Ashkenazi Jewish (ASJ)

AF:

0.563

AC:

13393

AN:

23780

East Asian (EAS)

AF:

0.339

AC:

13254

AN:

39068

South Asian (SAS)

AF:

0.525

AC:

42169

AN:

80304

European-Finnish (FIN)

AF:

0.585

AC:

28053

AN:

47950

Middle Eastern (MID)

AF:

0.624

AC:

2453

AN:

3932

European-Non Finnish (NFE)

AF:

0.562

AC:

594424

AN:

1057048

Other (OTH)

AF:

0.568

AC:

32594

AN:

57434

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.361

Heterozygous variant carriers

19688

39377

59065

78754

98442

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16448

32896

49344

65792

82240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.617

AC:

92807

AN:

150412

Hom.:

29273

Cov.:

AF XY:

0.615

AC XY:

45095

AN XY:

73350

show subpopulations

African (AFR)

AF:

0.717

AC:

29457

AN:

41062

American (AMR)

AF:

0.665

AC:

10059

AN:

15126

Ashkenazi Jewish (ASJ)

AF:

0.559

AC:

1932

AN:

3456

East Asian (EAS)

AF:

0.325

AC:

1641

AN:

5042

South Asian (SAS)

AF:

0.529

AC:

2525

AN:

4776

European-Finnish (FIN)

AF:

0.576

AC:

5891

AN:

10234

Middle Eastern (MID)

AF:

0.659

AC:

191

AN:

290

European-Non Finnish (NFE)

AF:

0.583

AC:

39289

AN:

67428

Other (OTH)

AF:

0.587

AC:

1225

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

1561

3121

4682

6242

7803

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

746

1492

2238

2984

3730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.599

Hom.:

5002

Bravo

AF:

0.623

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Isolated lutropin deficiency

Benign:3

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

1.4

(source)

DANN

Benign

0.12

PhyloP100

-0.52

PromoterAI

0.0038

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over