chr11-30233644-AGT-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_001382289.1(FSHB):c.236_237delTG(p.Val79GlufsTer27) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000558 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V79V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

FSHB
NM_001382289.1 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.69

Publications

0 publications found

Variant links:

Genes affected

FSHB (HGNC:3964): (follicle stimulating hormone subunit beta) The pituitary glycoprotein hormone family includes follicle-stimulating hormone, luteinizing hormone, chorionic gonadotropin, and thyroid-stimulating hormone. All of these glycoproteins consist of an identical alpha subunit and a hormone-specific beta subunit. This gene encodes the beta subunit of follicle-stimulating hormone. In conjunction with luteinizing hormone, follicle-stimulating hormone induces egg and sperm production. Alternative splicing results in two transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

FSHB links:

ARL14EP-DT (HGNC:55517): (ARL14EP divergent transcript)

ARL14EP-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-30233644-AGT-A is Pathogenic according to our data. Variant chr11-30233644-AGT-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382289.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FSHB	NM_001382289.1	MANE Select	c.236_237delTG	p.Val79GlufsTer27	frameshift	Exon 3 of 3	NP_001369218.1
FSHB	NM_000510.4		c.236_237delTG	p.Val79GlufsTer27	frameshift	Exon 3 of 3	NP_000501.1
FSHB	NM_001018080.3		c.236_237delTG	p.Val79GlufsTer27	frameshift	Exon 3 of 3	NP_001018090.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FSHB	ENST00000533718.2	TSL:1 MANE Select	c.236_237delTG	p.Val79GlufsTer27	frameshift	Exon 3 of 3	ENSP00000433424.1
FSHB	ENST00000254122.8	TSL:5	c.236_237delTG	p.Val79GlufsTer27	frameshift	Exon 3 of 3	ENSP00000254122.3
FSHB	ENST00000417547.1	TSL:5	c.236_237delTG	p.Val79GlufsTer27	frameshift	Exon 3 of 3	ENSP00000416606.1

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000957

AC:

AN:

250876

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000513

AC:

AN:

1461742

Hom.:

AF XY:

0.0000633

AC XY:

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00233

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111932

Other (OTH)

AF:

0.0000497

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000985

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000347

Hom.:

Bravo

AF:

0.000106

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 24 without anosmia

Pathogenic:2

Nov 25, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Aug 14, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The FSHB c.236_237delTG (p.Val79GlufsTer27) variant is a frameshift variant predicted to result in premature truncation of the protein. The p.Val79GlufsTer27 variant is reported in four studies in which it is found in a total of four individuals affected with follicle-stimulating hormone (FSH) deficiency, including in three in a homozygous state (Matthews et al. 1993; Matthews et al. 1997; Phillip et al. 1998) and in one in a compound heterozygous state (Layman et al. 1997). The p.Val79GlufsTer27 variant is also reported to be present in six unaffected family members in a heterozygous state (Matthews et al. 1993; Layman et al. 1997; Phillip et al. 1998). The variant is absent from 34 controls (Layman et al. 1997) but is reported at a frequency of 0.00224 in the Ashkenazi Jewish population of the Genome Aggregation Database. Transfection of the p.Val79GlufsTer27 variant into CHO cells, showed no expression of FSH (Layman et al. 1997). The predicted truncation eliminates the last five cysteine residues of the protein, which are believed to be important for dimer stabilization. Based on collective evidence, the p.Val79GlufsTer27 variant is classified as pathogenic for isolated follicle-stimulating hormone deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

not provided

Pathogenic:2

Jun 03, 2019

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 51 amino acids are lost and replaced with 26 incorrect amino acids (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 9624193, 8220432, 20488225, 9271483)

Aug 07, 2018

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the FSHB gene demonstrated a two base pair deletion in exon 3, c.236_237del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 26 amino acids downstream of the mutation, p.Val79Glufs*27. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated FSHB protein with potentially abnormal function. This sequence change has previously been described in the homozygous state in a female patient with infertility, primary amenorrhea, with undetectable serum FSH (PMID: 8220432). This variant is also reported to occur in the compound heterozygous state with a pathogenic missense variant in another patient with similar features (PMID: 9271483).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.7

Mutation Taster

=5/195

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over