Genetic Variant FSHR:p.Ser680Thr (chr2-48962781-AC-CG) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_000145.4(FSHR):c.2039_2040delGTinsCG (p.Ser680Thr) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S680N: Benign (ClinVar VariationId 16247, 2 stars)

Frequency

Genomes: not found (cov: 32)

Consequence

FSHR
NM_000145.4 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.491

Publications

0 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:

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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: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000279 by highest known P/LP ClinVar AF 0.000279) — PM2 moderate.

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.2039_2040delGTinsCG p.Ser680Thr	missense	N/A	Prot: NP_000136.2
	FSHR NM_181446.3		c.1961_1962delGTinsCG p.Ser654Thr	missense	N/A	Prot: NP_852111.2 UniProt: P23945-3

FSHR NM_000145.4

MANE Select

HGVSc / HGVSpc.2039_2040delGTinsCGp.Ser680Thr

Exon rankN/A

missense

Prot: NP_000136.2

FSHR NM_181446.3

HGVSc / HGVSpc.1961_1962delGTinsCGp.Ser654Thr

Exon rankN/A

missense

Prot: NP_852111.2UniProt: P23945-3

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
FSHR ENST00000406846.7	TSL:1MANE Select	c.2039_2040delGTinsCG p.Ser680Thr	missense	N/A	Prot: ENSP00000384708.2 UniProt: P23945-1
FSHR ENST00000304421.8	TSL:1	c.1961_1962delGTinsCG p.Ser654Thr	missense	N/A	Prot: ENSP00000306780.4 UniProt: P23945-3
MIR548BAHG ENST00000634588.1	TSL:5	n.492+16376_492+16377delACinsCG	intron	Intron 2 of 4	Prot:

FSHR ENST00000406846.7

TSL:1MANE Select

HGVSc / HGVSpc.2039_2040delGTinsCGp.Ser680Thr

Exon rankN/A

missense

Prot: ENSP00000384708.2UniProt: P23945-1

FSHR ENST00000304421.8

TSL:1

HGVSc / HGVSpc.1961_1962delGTinsCGp.Ser654Thr

Exon rankN/A

missense

Prot: ENSP00000306780.4UniProt: P23945-3

MIR548BAHG ENST00000634588.1

TSL:5

HGVSc / HGVSpn.492+16376_492+16377delACinsCG

Exon rankIntron 2 of 4

intron

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	0.49

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

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

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence