rs121909665

Positions:

• chr2-48990629-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_Moderate PM2 PP3_Moderate PP5

The NM_000145.4(FSHR):​c.383C>A​(p.Ser128Tyr) 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FSHR NM_000145.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.72

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 Likely_pathogenic. Variant got 7 ACMG points.

• PS1: Transcript NM_000145.4 (FSHR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868
• PP5: Variant 2-48990629-G-T is Pathogenic according to our data. Variant chr2-48990629-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 16254.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FSHR	NM_000145.4	c.383C>A	p.Ser128Tyr	missense_variant	5/10	ENST00000406846.7	NP_000136.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FSHR	ENST00000406846.7	c.383C>A	p.Ser128Tyr	missense_variant	5/10	1	NM_000145.4	ENSP00000384708	P1
	ENST00000634588.1	n.492+44224G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1452200 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 723244

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Ovarian hyperstimulation syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T;.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.49	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.2	N;N;D
REVEL	Pathogenic	0.78
Sift	Benign	0.86	T;T;D
Sift4G	Benign	0.99	T;T;.
Vest4		0.80
MutPred		0.78		Gain of methylation at K133 (P = 0.0628);Gain of methylation at K133 (P = 0.0628);Gain of methylation at K133 (P = 0.0628);
MVP		1.0
MPC		0.13
ClinPred		0.97	D
GERP RS		5.2
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909665; hg19: chr2-49217768;