chr2-48962782-C-A

Variant names:

• chr2-48962782-C-A
• rs6166
• NM_000145.4:c.2039G>T
• FSHR p.Ser680Ile

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_000145.4(FSHR):c.2039G>T (p.Ser680Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0530
• Publications: 283 publications found

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

MIR548BAHG (HGNC:58158): ()

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

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.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (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.2039G>T p.Ser680Ile	missense	Exon 10 of 10	Prot: NP_000136.2
	FSHR NM_181446.3		c.1961G>T p.Ser654Ile	missense	Exon 9 of 9	Prot: NP_852111.2 UniProt:

FSHR NM_000145.4

MANE Select

HGVSc / HGVSpc.2039G>Tp.Ser680Ile

Exon rankExon 10 of 10

missense

Prot: NP_000136.2

FSHR NM_181446.3

HGVSc / HGVSpc.1961G>Tp.Ser654Ile

Exon rankExon 9 of 9

missense

Prot: NP_852111.2UniProt: P23945-3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FSHR ENST00000406846.7	TSL:1MANE Select	c.2039G>T p.Ser680Ile	missense	Exon 10 of 10	Prot: ENSP00000384708.2 UniProt:
	FSHR ENST00000304421.8	TSL:1	c.1961G>T p.Ser654Ile	missense	Exon 9 of 9	Prot: ENSP00000306780.4 UniProt:
	MIR548BAHG ENST00000634588.1	TSL:5	n.492+16377C>A	intron	Intron 2 of 4	Prot:

FSHR ENST00000406846.7

TSL:1MANE Select

HGVSc / HGVSpc.2039G>Tp.Ser680Ile

Exon rankExon 10 of 10

missense

Prot: ENSP00000384708.2UniProt: P23945-1

FSHR ENST00000304421.8

TSL:1

HGVSc / HGVSpc.1961G>Tp.Ser654Ile

Exon rankExon 9 of 9

missense

Prot: ENSP00000306780.4UniProt: P23945-3

MIR548BAHG ENST00000634588.1

TSL:5

HGVSc / HGVSpn.492+16377C>A

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:48
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	3.3
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.4
DANN	Uncertain	0.98
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.38	N
FuncVEP CTI	Benign	0.20
GPN-Star LLR	N/A	-1.9
GPN-Star score	N/A	1.9
LIST_S2	Benign	0.33	T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.83	T
Mutation Taster	N/A	87/13	polymorphism
PhyloP100	Benign	0.053
popEVE	Benign	-3.0
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.069
Sift	Benign	0.055	T
Sift4G	Benign	0.17	T
VESM-3B	Benign	-5.8

Showing 25 of 25 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

Other links and lift over

dbSNP: rs6166;

hg19: chr2-49189921;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar