2-48962477-G-A

Position:

• chr2-48962477-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000145.4(FSHR):​c.*256C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 454,662 control chromosomes in the GnomAD database, including 207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (168 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (39 hom.)
• Consequence: FSHR NM_000145.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.128

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-48962477-G-A is Benign according to our data. Variant chr2-48962477-G-A is described in ClinVar as [Benign]. Clinvar id is 336475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.081 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FSHR	NM_000145.4	c.*256C>T		3_prime_UTR_variant	10/10	ENST00000406846.7	NP_000136.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FSHR	ENST00000406846	c.*256C>T		3_prime_UTR_variant	10/10	1	NM_000145.4	ENSP00000384708.2
ENSG00000282890	ENST00000634588.1	n.492+16072G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3923 AN: 152056 Hom.: 166 Cov.: 32

Gnomad AFR AF: 0.0835

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.0244

GnomAD4 exome AF: 0.00442 AC: 1338 AN: 302488 Hom.: 39 Cov.: 3 AF XY: 0.00371 AC XY: 602 AN XY: 162186

Gnomad4 AFR exome AF: 0.0845

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.00593

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000385

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.00948

GnomAD4 genome AF: 0.0258 AC: 3924 AN: 152174 Hom.: 168 Cov.: 32 AF XY: 0.0257 AC XY: 1910 AN XY: 74400

Gnomad4 AFR AF: 0.0833

Gnomad4 AMR AF: 0.0189

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.0242

Alfa AF: 0.0179 Hom.: 11

Bravo AF: 0.0305

Asia WGS AF: 0.00520 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Ovarian dysgenesis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Ovarian hyperstimulation syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.9
DANN	Benign	0.23

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: rs72873077; hg19: chr2-49189616;