rs72825259

Variant names:

• chr2-48962487-A-T
• rs72825259
• NM_000145.4:c.*246T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000145.4(FSHR):​c.*246T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0261 in 487,370 control chromosomes in the GnomAD database, including 248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (55 hom., cov: 32)
  • Exomes 𝑓: 0.028 (193 hom.)
• Consequence: FSHR NM_000145.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.63
• Publications: 0 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

MIR548BAHG (HGNC:58158):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-48962487-A-T is Benign according to our data. Variant chr2-48962487-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 336476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0213 (3244/152330) while in subpopulation SAS AF = 0.033 (159/4824). AF 95% confidence interval is 0.0309. There are 55 homozygotes in GnomAd4. There are 1600 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 55 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000145.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FSHR	NM_000145.4	MANE Select	c.*246T>A		3_prime_UTR	Exon 10 of 10	NP_000136.2
	FSHR	NM_181446.3		c.*246T>A		3_prime_UTR	Exon 9 of 9	NP_852111.2	P23945-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FSHR	ENST00000406846.7	TSL:1 MANE Select	c.*246T>A		3_prime_UTR	Exon 10 of 10	ENSP00000384708.2	P23945-1
	MIR548BAHG	ENST00000634588.1	TSL:5	n.492+16082A>T		intron	N/A
	FSHR	ENST00000304421.8	TSL:1	c.*246T>A		downstream_gene	N/A	ENSP00000306780.4	P23945-3

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3248 AN: 152212 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.00576

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0336

Gnomad FIN AF: 0.0228

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0320

Gnomad OTH AF: 0.0220

GnomAD4 exome AF: 0.0282 AC: 9453 AN: 335040 Hom.: 193 Cov.: 3 AF XY: 0.0290 AC XY: 5177 AN XY: 178592

African (AFR) AF: 0.00565 AC: 57 AN: 10082

American (AMR) AF: 0.0148 AC: 202 AN: 13628

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 248 AN: 10234

East Asian (EAS) AF: 0.000245 AC: 5 AN: 20410

South Asian (SAS) AF: 0.0348 AC: 1379 AN: 39580

European-Finnish (FIN) AF: 0.0255 AC: 453 AN: 17766

Middle Eastern (MID) AF: 0.0513 AC: 72 AN: 1404

European-Non Finnish (NFE) AF: 0.0322 AC: 6543 AN: 202996

Other (OTH) AF: 0.0261 AC: 494 AN: 18940

GnomAD4 genome AF: 0.0213 AC: 3244 AN: 152330 Hom.: 55 Cov.: 32 AF XY: 0.0215 AC XY: 1600 AN XY: 74494

African (AFR) AF: 0.00575 AC: 239 AN: 41588

American (AMR) AF: 0.0184 AC: 282 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.0330 AC: 159 AN: 4824

European-Finnish (FIN) AF: 0.0228 AC: 242 AN: 10618

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0320 AC: 2175 AN: 68030

Other (OTH) AF: 0.0218 AC: 46 AN: 2114

Alfa AF: 0.0254 Hom.: 9

Bravo AF: 0.0192

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Ovarian dysgenesis 1 (1)
-	-	1	Ovarian hyperstimulation syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.4
DANN	Benign	0.56
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

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: rs72825259; hg19: chr2-49189626;