2-48963476-T-C

Variant names:

• chr2-48963476-T-C
• rs121909663
• NM_000145.4:c.1345A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3 PP5

The NM_000145.4(FSHR):​c.1345A>G​(p.Thr449Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T449I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FSHR NM_000145.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.01
• Publications: 18 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)
• ovarian dysgenesis 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 46 XX gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000282890 (HGNC:58158):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-48963475-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16249.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: -0.79874 (below the threshold of 3.09). Trascript score misZ: -0.97417 (below the threshold of 3.09). GenCC associations: The gene is linked to ovarian hyperstimulation syndrome, ovarian dysgenesis 1, 46 XX gonadal dysgenesis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766
• PP5: Variant 2-48963476-T-C is Pathogenic according to our data. Variant chr2-48963476-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 16252.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FSHR	NM_000145.4	c.1345A>G	p.Thr449Ala	missense_variant	Exon 10 of 10	ENST00000406846.7	NP_000136.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FSHR	ENST00000406846.7	c.1345A>G	p.Thr449Ala	missense_variant	Exon 10 of 10	1	NM_000145.4	ENSP00000384708.2
FSHR	ENST00000304421.8	c.1267A>G	p.Thr423Ala	missense_variant	Exon 9 of 9	1		ENSP00000306780.4
ENSG00000282890	ENST00000634588.1	n.492+17071T>C		intron_variant	Intron 2 of 4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Ovarian hyperstimulation syndrome Pathogenic:1

Apr 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;.
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.27	D
PhyloP100		5.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.0030	D;D
Vest4		0.46
MutPred		0.91		Gain of catalytic residue at T449 (P = 0.057);.;
MVP		1.0
MPC		0.045
ClinPred		0.96	D
GERP RS		5.6
gMVP		0.79
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909663; hg19: chr2-49190615;