2-48963902-C-G

Position:

• chr2-48963902-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000145.4(FSHR):​c.919G>C​(p.Ala307Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A307T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FSHR NM_000145.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0220

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]

ENSG00000282890 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0831517).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FSHR	NM_000145.4	c.919G>C	p.Ala307Pro	missense_variant	10/10	ENST00000406846.7	NP_000136.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FSHR	ENST00000406846.7	c.919G>C	p.Ala307Pro	missense_variant	10/10	1	NM_000145.4	ENSP00000384708.2
FSHR	ENST00000304421.8	c.841G>C	p.Ala281Pro	missense_variant	9/9	1		ENSP00000306780.4
FSHR	ENST00000454032.5	c.733G>C	p.Ala245Pro	missense_variant	9/9	1		ENSP00000415504.1
ENSG00000282890	ENST00000634588.1	n.492+17497C>G		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250846 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135542

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461768 Hom.: 0 Cov.: 44 AF XY: 0.00000550 AC XY: 4 AN XY: 727184

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Benign	0.96
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.58	T;.;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.083	T;T;T
MetaSVM	Benign	-0.96	T
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.31	N;N;N
REVEL	Benign	0.065
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.35	T;T;.
Vest4		0.13
MutPred		0.37		Gain of disorder (P = 0.0513);.;.;
MVP		0.84
MPC		0.027
ClinPred		0.039	T
GERP RS		1.8
gMVP		0.75

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: rs6165; hg19: chr2-49191041;