chr11-30233644-AGT-A

Position:

chr11-30233644-AGT-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_001382289.1(FSHB):c.236_237del(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 (★★).

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

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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. Fraction of 0.397 CDS is truncated, and there are 2 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 [Likely_pathogenic]. Clinvar id is 16240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-30233644-AGT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FSHB	NM_001382289.1 linkuse as main transcript	c.236_237del	p.Val79GlufsTer27	frameshift_variant	3/3	ENST00000533718.2	NP_001369218.1
ARL14EP-DT	XR_007062639.1 linkuse as main transcript	n.351+83244_351+83245del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
FSHB	ENST00000533718.2 linkuse as main transcript	c.236_237del	p.Val79GlufsTer27	frameshift_variant	3/3	1	NM_001382289.1	ENSP00000433424	P1
ARL14EP-DT	ENST00000662729.1 linkuse as main transcript	n.293-76793_293-76792del		intron_variant, non_coding_transcript_variant
FSHB	ENST00000254122.8 linkuse as main transcript	c.236_237del	p.Val79GlufsTer27	frameshift_variant	3/3	5		ENSP00000254122	P1
FSHB	ENST00000417547.1 linkuse as main transcript	c.236_237del	p.Val79GlufsTer27	frameshift_variant	3/3	5		ENSP00000416606	P1

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

GnomAD3 exomes

AF:

0.0000957

AC:

AN:

250876

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135548

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00233

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 25, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 14, 2018	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

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 07, 2018	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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2019	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) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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