11-30231961-G-T

Position:

chr11-30231961-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001382289.1(FSHB):c.59G>T(p.Ser20Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,613,922 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 9 hom. )

Consequence

FSHB
NM_001382289.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.828

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:):

ARL14EP-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018245697).

BP6

Variant 11-30231961-G-T is Benign according to our data. Variant chr11-30231961-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 304276.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FSHB	NM_001382289.1 linkuse as main transcript	c.59G>T	p.Ser20Ile	missense_variant	2/3	ENST00000533718.2	NP_001369218.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FSHB	ENST00000533718.2 linkuse as main transcript	c.59G>T	p.Ser20Ile	missense_variant	2/3	1	NM_001382289.1	ENSP00000433424.1	P01225
FSHB	ENST00000254122.8 linkuse as main transcript	c.59G>T	p.Ser20Ile	missense_variant	2/3	5		ENSP00000254122.3	P01225
FSHB	ENST00000417547.1 linkuse as main transcript	c.59G>T	p.Ser20Ile	missense_variant	2/3	5		ENSP00000416606.1	P01225
ARL14EP-DT	ENST00000662729.1 linkuse as main transcript	n.293-75108C>A		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00226

AC:

344

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00310

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00218

AC:

546

AN:

251002

Hom.:

AF XY:

0.00229

AC XY:

310

AN XY:

135626

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.00855

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00313

Gnomad OTH exome

AF:

0.00327

GnomAD4 exome

AF:

0.00246

AC:

3596

AN:

1461650

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

1767

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.00215

Gnomad4 ASJ exome

AF:

0.00850

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.000281

Gnomad4 NFE exome

AF:

0.00275

Gnomad4 OTH exome

AF:

0.00265

GnomAD4 genome

AF:

0.00226

AC:

344

AN:

152272

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00360

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00310

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00304

Hom.:

Bravo

AF:

0.00258

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00229

AC:

278

EpiCase

AF:

0.00365

EpiControl

AF:

0.00350

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2024

- -

FSHB-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.77

D;D;D

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.065

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.67

.;.;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.018

T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.2

L;L;L

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.93

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.43

T;T;T

Polyphen

0.0060

B;B;B

Vest4

0.11

MVP

0.96

MPC

0.28

ClinPred

0.011

GERP RS

4.9

Varity_R

0.26

gMVP

0.75

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