2-48983125-G-A

Position:

• chr2-48983125-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PS1_Moderate PP3 PP5 BP4

The NM_000145.4(FSHR):​c.566C>T​(p.Ala189Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: FSHR NM_000145.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.57

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PS1: Transcript NM_000145.4 (FSHR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PP3: Multiple lines of computational evidence support a deleterious effect 6: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 2-48983125-G-A is Pathogenic according to our data. Variant chr2-48983125-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16243.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-48983125-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.019185185). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FSHR	NM_000145.4	c.566C>T	p.Ala189Val	missense_variant	7/10	ENST00000406846.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FSHR	ENST00000406846.7	c.566C>T	p.Ala189Val	missense_variant	7/10	1	NM_000145.4	P1
	ENST00000634588.1	n.492+36720G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00792

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000692 AC: 174 AN: 251362 Hom.: 0 AF XY: 0.000670 AC XY: 91 AN XY: 135836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00753

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000250 AC: 365 AN: 1461814 Hom.: 0 Cov.: 31 AF XY: 0.000248 AC XY: 180 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00650

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000559 AC: 85 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.000888 AC XY: 66 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00792

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000446 Hom.: 40

Bravo AF: 0.0000227

ExAC AF: 0.000618 AC: 75

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Ovarian dysgenesis 1 Pathogenic:2

Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000145.3:c.566C>T in the FSHR gene has an allele frequency of 0.007 in European (Finnish) subpopulation in the gnomAD database. The p.Ala189Val (NM_000145.3:c.566C>T) variant in FSHR has been reported as founder mutation in Finnish population(PMID: 11754099), and segregated in over 10 affected siblings in 6 families (PMID: 7553856). Expression of the gene in transfected cells demonstrated a dramatic reduction of binding capacity and signal transduction, but apparently normal ligand-binding affinity of the mutated receptor (PMID: 7553856). Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationTaster, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PS4, PP3, PS3, PP1_Strong. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2002	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;.;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.019	T;T;T
MetaSVM	Uncertain	0.62	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D;T
Sift4G	Uncertain	0.030	D;D;.
Vest4		0.94
MVP		1.0
MPC		0.19
ClinPred		0.39	T
GERP RS		5.5
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs121909658; hg19: chr2-49210264;