2-49020693-T-C

Variant names:

• chr2-49020693-T-C
• rs2349415
• NM_000145.4:c.225-533A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000145.4(FSHR):​c.225-533A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 152,022 control chromosomes in the GnomAD database, including 30,836 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.63 (30836 hom., cov: 31)
• Consequence: FSHR NM_000145.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42
• Publications: 25 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FSHR	NM_000145.4	c.225-533A>G		intron_variant	Intron 2 of 9	ENST00000406846.7	NP_000136.2
FSHR	NM_181446.3	c.225-533A>G		intron_variant	Intron 2 of 8		NP_852111.2
FSHR	XM_011532733.3	c.225-533A>G		intron_variant	Intron 2 of 10		XP_011531035.1
FSHR	XM_011532740.1	c.225-533A>G		intron_variant	Intron 2 of 10		XP_011531042.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FSHR	ENST00000406846.7	c.225-533A>G		intron_variant	Intron 2 of 9	1	NM_000145.4	ENSP00000384708.2

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96258 AN: 151904 Hom.: 30817 Cov.: 31

Gnomad AFR AF: 0.542

Gnomad AMI AF: 0.606

Gnomad AMR AF: 0.689

Gnomad ASJ AF: 0.652

Gnomad EAS AF: 0.779

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.671

Gnomad MID AF: 0.624

Gnomad NFE AF: 0.660

Gnomad OTH AF: 0.650

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.634 AC: 96315 AN: 152022 Hom.: 30836 Cov.: 31 AF XY: 0.634 AC XY: 47094 AN XY: 74290

African (AFR) AF: 0.542 AC: 22441 AN: 41438

American (AMR) AF: 0.689 AC: 10525 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 2261 AN: 3470

East Asian (EAS) AF: 0.779 AC: 4021 AN: 5160

South Asian (SAS) AF: 0.623 AC: 3001 AN: 4816

European-Finnish (FIN) AF: 0.671 AC: 7095 AN: 10566

Middle Eastern (MID) AF: 0.616 AC: 180 AN: 292

European-Non Finnish (NFE) AF: 0.660 AC: 44871 AN: 67990

Other (OTH) AF: 0.647 AC: 1367 AN: 2112

Alfa AF: 0.650 Hom.: 42055

Bravo AF: 0.634

Asia WGS AF: 0.696 AC: 2421 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.54
DANN	Benign	0.56
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs2349415; hg19: chr2-49247832;