2-48963902-C-T

Position:

chr2-48963902-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000406846.7(FSHR):c.919G>A(p.Ala307Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 1,613,318 control chromosomes in the GnomAD database, including 240,465 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 18808 hom., cov: 31)

Exomes 𝑓: 0.55 ( 221657 hom. )

Consequence

FSHR
ENST00000406846.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0220

Variant links:

Genes affected

FSHR (HGNC:3969): (follicle stimulating hormone receptor) The protein encoded by this gene belongs to family 1 of G-protein coupled receptors. It is the receptor for follicle stimulating hormone and functions in gonad development. Mutations in this gene cause ovarian dysgenesis type 1, and also ovarian hyperstimulation syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

FSHR links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.7555785E-6).

BP6

Variant 2-48963902-C-T is Benign according to our data. Variant chr2-48963902-C-T is described in ClinVar as [Benign]. Clinvar id is 16246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-48963902-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FSHR	NM_000145.4 linkuse as main transcript	c.919G>A	p.Ala307Thr	missense_variant	10/10	ENST00000406846.7	NP_000136.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
FSHR	ENST00000406846.7 linkuse as main transcript	c.919G>A	p.Ala307Thr	missense_variant	10/10	1	NM_000145.4	ENSP00000384708	P1
FSHR	ENST00000304421.8 linkuse as main transcript	c.841G>A	p.Ala281Thr	missense_variant	9/9	1		ENSP00000306780
FSHR	ENST00000454032.5 linkuse as main transcript	c.733G>A	p.Ala245Thr	missense_variant	9/9	1		ENSP00000415504
	ENST00000634588.1 linkuse as main transcript	n.492+17497C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.480

AC:

72918

AN:

151824

Hom.:

18810

Cov.:

show subpopulations

Gnomad AFR

AF:

0.281

Gnomad AMI

AF:

0.489

Gnomad AMR

AF:

0.582

Gnomad ASJ

AF:

0.472

Gnomad EAS

AF:

0.666

Gnomad SAS

AF:

0.552

Gnomad FIN

AF:

0.552

Gnomad MID

AF:

0.415

Gnomad NFE

AF:

0.549

Gnomad OTH

AF:

0.492

GnomAD3 exomes

AF:

0.553

AC:

138761

AN:

250846

Hom.:

39692

AF XY:

0.552

AC XY:

74841

AN XY:

135542

show subpopulations

Gnomad AFR exome

AF:

0.274

Gnomad AMR exome

AF:

0.691

Gnomad ASJ exome

AF:

0.468

Gnomad EAS exome

AF:

0.651

Gnomad SAS exome

AF:

0.538

Gnomad FIN exome

AF:

0.555

Gnomad NFE exome

AF:

0.547

Gnomad OTH exome

AF:

0.556

GnomAD4 exome

AF:

0.548

AC:

800618

AN:

1461376

Hom.:

221657

Cov.:

AF XY:

0.547

AC XY:

397799

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.276

Gnomad4 AMR exome

AF:

0.674

Gnomad4 ASJ exome

AF:

0.463

Gnomad4 EAS exome

AF:

0.643

Gnomad4 SAS exome

AF:

0.534

Gnomad4 FIN exome

AF:

0.555

Gnomad4 NFE exome

AF:

0.551

Gnomad4 OTH exome

AF:

0.536

GnomAD4 genome

AF:

0.480

AC:

72927

AN:

151942

Hom.:

18808

Cov.:

AF XY:

0.483

AC XY:

35853

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.281

Gnomad4 AMR

AF:

0.582

Gnomad4 ASJ

AF:

0.472

Gnomad4 EAS

AF:

0.666

Gnomad4 SAS

AF:

0.550

Gnomad4 FIN

AF:

0.552

Gnomad4 NFE

AF:

0.549

Gnomad4 OTH

AF:

0.488

Alfa

AF:

0.536

Hom.:

48401

Bravo

AF:

0.476

TwinsUK

AF:

0.551

AC:

2042

ALSPAC

AF:

0.550

AC:

2119

ESP6500AA

AF:

0.285

AC:

1256

ESP6500EA

AF:

0.542

AC:

4657

ExAC

AF:

0.544

AC:

66106

Asia WGS

AF:

0.562

AC:

1953

AN:

3478

EpiCase

AF:

0.538

EpiControl

AF:

0.540

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ovarian dysgenesis 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Ovarian hyperstimulation syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28547204, 26291798, 16574671, 23139742, 20399696, 18591890, 23536150, 18321487, 19550076) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.69

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.55

T;.;T

MetaRNN

Benign

0.0000058

T;T;T

MetaSVM

Benign

-0.93

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.070

N;N;N

REVEL

Benign

0.049

Sift

Benign

0.45

T;T;T

Sift4G

Benign

0.64

T;T;.

Vest4

0.029

MPC

0.023

ClinPred

0.0080

GERP RS

1.8

gMVP

0.56

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