11-30233644-AGT-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_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 (★★). 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.69

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]

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

ACMG classification

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. There are 5 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	UniProt
FSHB	NM_001382289.1	c.236_237del	p.Val79GlufsTer27	frameshift_variant	3/3	ENST00000533718.2
ARL14EP-DT	XR_007062639.1	n.351+83244_351+83245del		intron_variant, non_coding_transcript_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152212 Hom.: 0 Cov.: 32

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: 24 AN: 250876 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135548

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: 75 AN: 1461742 Hom.: 0 AF XY: 0.0000633 AC XY: 46 AN XY: 727178

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: 15 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74362

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.: 0

Bravo AF: 0.000106

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

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

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) -
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). -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs5030646; hg19: chr11-30255191;