11-30233722-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001382289.1(FSHB):c.312G>A(p.Lys104=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,614,070 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (44 hom.)
• Consequence: FSHB NM_001382289.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.00300

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 11-30233722-G-A is Benign according to our data. Variant chr11-30233722-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 880521.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.003 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FSHB	NM_001382289.1	c.312G>A	p.Lys104=	synonymous_variant	3/3	ENST00000533718.2
ARL14EP-DT	XR_007062639.1	n.351+83168C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FSHB	ENST00000533718.2	c.312G>A	p.Lys104=	synonymous_variant	3/3	1	NM_001382289.1	P1
ARL14EP-DT	ENST00000662729.1	n.293-76869C>T		intron_variant, non_coding_transcript_variant
FSHB	ENST00000254122.8	c.312G>A	p.Lys104=	synonymous_variant	3/3	5		P1
FSHB	ENST00000417547.1	c.312G>A	p.Lys104=	synonymous_variant	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.00354 AC: 539 AN: 152230 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0435

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00416 AC: 1044 AN: 250828 Hom.: 23 AF XY: 0.00399 AC XY: 541 AN XY: 135520

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.000382

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0398

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.00425

GnomAD4 exome AF: 0.00180 AC: 2628 AN: 1461722 Hom.: 44 Cov.: 32 AF XY: 0.00176 AC XY: 1278 AN XY: 727176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00134

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0374

Gnomad4 NFE exome AF: 0.000416

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00354 AC: 539 AN: 152348 Hom.: 13 Cov.: 32 AF XY: 0.00513 AC XY: 382 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0435

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000287

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypogonadotropic hypogonadism 24 without anosmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	8.5
Dann	Benign	0.62

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: rs34365964; hg19: chr11-30255269;