FSHR p.Ser680Asn

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6_Strong

The NM_000145.4(FSHR):c.2039G>A (p.Ser680Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.558 (AC=900,176) in the gnomAD database across 1,613,272 control chromosomes, including 252,236 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.661. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.57 ( 24652 hom., cov: 32)

Exomes 𝑓: 0.56 ( 227584 hom. )

Consequence

FSHR
NM_000145.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0530

Publications

379 publications found

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 Gene-Disease associations (from GenCC):

ovarian hyperstimulation syndrome
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
ovarian dysgenesis 1
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
46 XX gonadal dysgenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FSHR links:

MIR548BAHG (HGNC:58158):

MIR548BAHG links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000145.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -14 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.6607 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000145.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FSHR	NM_000145.4	MANE Select	c.2039G>A	p.Ser680Asn	missense	Exon 10 of 10	NP_000136.2
	FSHR	NM_181446.3		c.1961G>A	p.Ser654Asn	missense	Exon 9 of 9	NP_852111.2	P23945-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FSHR	ENST00000406846.7	TSL:1 MANE Select	c.2039G>A	p.Ser680Asn	missense	Exon 10 of 10	ENSP00000384708.2	P23945-1
FSHR	ENST00000304421.8	TSL:1	c.1961G>A	p.Ser654Asn	missense	Exon 9 of 9	ENSP00000306780.4	P23945-3
MIR548BAHG	ENST00000634588.1	TSL:5	n.492+16377C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.568

AC:

86242

AN:

151908

Hom.:

24645

Cov.:

show subpopulations

Gnomad AFR

AF:

0.583

Gnomad AMI

AF:

0.515

Gnomad AMR

AF:

0.602

Gnomad ASJ

AF:

0.481

Gnomad EAS

AF:

0.680

Gnomad SAS

AF:

0.562

Gnomad FIN

AF:

0.552

Gnomad MID

AF:

0.481

Gnomad NFE

AF:

0.551

Gnomad OTH

AF:

0.556

GnomAD2 exomes

AF:

0.574

AC:

144230

AN:

251060

AF XY:

0.569

show subpopulations

Gnomad AFR exome

AF:

0.592

Gnomad AMR exome

AF:

0.671

Gnomad ASJ exome

AF:

0.476

Gnomad EAS exome

AF:

0.669

Gnomad FIN exome

AF:

0.556

Gnomad NFE exome

AF:

0.548

Gnomad OTH exome

AF:

0.566

GnomAD4 exome

AF:

0.557

AC:

813884

AN:

1461246

Hom.:

227584

Cov.:

AF XY:

0.555

AC XY:

403744

AN XY:

726958

show subpopulations

African (AFR)

AF:

0.589

AC:

19699

AN:

33468

American (AMR)

AF:

0.659

AC:

29452

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.471

AC:

12314

AN:

26134

East Asian (EAS)

AF:

0.656

AC:

26024

AN:

39688

South Asian (SAS)

AF:

0.542

AC:

46739

AN:

86254

European-Finnish (FIN)

AF:

0.555

AC:

29661

AN:

53418

Middle Eastern (MID)

AF:

0.510

AC:

2939

AN:

5764

European-Non Finnish (NFE)

AF:

0.552

AC:

613307

AN:

1111428

Other (OTH)

AF:

0.559

AC:

33749

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

19909

39818

59727

79636

99545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17324

34648

51972

69296

86620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.568

AC:

86292

AN:

152026

Hom.:

24652

Cov.:

AF XY:

0.567

AC XY:

42132

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.583

AC:

24186

AN:

41456

American (AMR)

AF:

0.602

AC:

9197

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.481

AC:

1668

AN:

3466

East Asian (EAS)

AF:

0.679

AC:

3514

AN:

5172

South Asian (SAS)

AF:

0.561

AC:

2701

AN:

4818

European-Finnish (FIN)

AF:

0.552

AC:

5828

AN:

10552

Middle Eastern (MID)

AF:

0.490

AC:

144

AN:

294

European-Non Finnish (NFE)

AF:

0.550

AC:

37415

AN:

67966

Other (OTH)

AF:

0.554

AC:

1169

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1928

3857

5785

7714

9642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

740

1480

2220

2960

3700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.556

Hom.:

108435

Bravo

AF:

0.574

Asia WGS

AF:

0.588

AC:

2045

AN:

3478

EpiCase

AF:

0.540

EpiControl

AF:

0.543

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.651

AC:

79969

AN:

122806

Turkish Variome

AF:

0.502

AC:

3372

AN:

6722

Hom.:

866

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.682

AC:

6110

AN:

8960

Hom.:

2082

ABraOM SABE-WGS-1171

AF:

0.577

AC:

1352

AN:

2342

Hom.:

396

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ovarian hyperstimulation syndrome (3)

not provided (2)

Ovarian dysgenesis 1 (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.29

(source)

DANN

Benign

0.18

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.0068

LIST_S2

Benign

0.11

MetaRNN

Benign

0.0000060

MetaSVM

Benign

-0.92

PhyloP100

0.053

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.38

REVEL

Benign

0.033

Sift

Benign

0.97

Sift4G

Benign

0.71

gMVP

0.30

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over