2-48974189-A-G

Variant names:

• chr2-48974189-A-G
• rs2268363
• NM_000145.4:c.669-5306T>C

Variant summary

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

The NM_000145.4(FSHR):​c.669-5306T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 152,094 control chromosomes in the GnomAD database, including 5,024 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 0.22 (5024 hom., cov: 32)
• Consequence: FSHR NM_000145.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.427
• Publications: 29 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FSHR	NM_000145.4	c.669-5306T>C		intron_variant	Intron 8 of 9	ENST00000406846.7	NP_000136.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FSHR	ENST00000406846.7	c.669-5306T>C		intron_variant	Intron 8 of 9	1	NM_000145.4	ENSP00000384708.2

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33830 AN: 151976 Hom.: 5014 Cov.: 32

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.199

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

GnomAD4 genome AF: 0.223 AC: 33892 AN: 152094 Hom.: 5024 Cov.: 32 AF XY: 0.222 AC XY: 16498 AN XY: 74342

African (AFR) AF: 0.425 AC: 17643 AN: 41466

American (AMR) AF: 0.139 AC: 2125 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 616 AN: 3470

East Asian (EAS) AF: 0.227 AC: 1170 AN: 5156

South Asian (SAS) AF: 0.146 AC: 704 AN: 4814

European-Finnish (FIN) AF: 0.169 AC: 1785 AN: 10592

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9290 AN: 67998

Other (OTH) AF: 0.204 AC: 432 AN: 2114

Alfa AF: 0.162 Hom.: 11239

Bravo AF: 0.230

Asia WGS AF: 0.208 AC: 725 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.82
PhyloP100		0.43
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: rs2268363; hg19: chr2-49201328;