2-49154446-C-T

Position:

• chr2-49154446-C-T

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.-29G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 1,609,736 control chromosomes in the GnomAD database, including 70,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6505 hom., cov: 31)
  • Exomes 𝑓: 0.29 (64028 hom.)
• Consequence: FSHR NM_000145.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.730

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 2-49154446-C-T is Benign according to our data. Variant chr2-49154446-C-T is described in ClinVar as [Benign]. Clinvar id is 137403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FSHR	NM_000145.4	c.-29G>A		5_prime_UTR_variant	1/10	ENST00000406846.7
FSHR	NM_181446.3	c.-29G>A		5_prime_UTR_variant	1/9
FSHR	XM_011532733.3	c.-29G>A		5_prime_UTR_variant	1/11
FSHR	XM_011532740.1	c.-29G>A		5_prime_UTR_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FSHR	ENST00000406846.7	c.-29G>A		5_prime_UTR_variant	1/10	1	NM_000145.4	P1
	ENST00000634588.1	n.492+208041C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43353 AN: 151800 Hom.: 6493 Cov.: 31

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.286

GnomAD3 exomes AF: 0.322 AC: 80116 AN: 249064 Hom.: 14134 AF XY: 0.315 AC XY: 42448 AN XY: 134620

Gnomad AFR exome AF: 0.256

Gnomad AMR exome AF: 0.489

Gnomad ASJ exome AF: 0.219

Gnomad EAS exome AF: 0.478

Gnomad SAS exome AF: 0.341

Gnomad FIN exome AF: 0.272

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.287

GnomAD4 exome AF: 0.290 AC: 422620 AN: 1457818 Hom.: 64028 Cov.: 33 AF XY: 0.291 AC XY: 210771 AN XY: 725280

Gnomad4 AFR exome AF: 0.248

Gnomad4 AMR exome AF: 0.473

Gnomad4 ASJ exome AF: 0.216

Gnomad4 EAS exome AF: 0.480

Gnomad4 SAS exome AF: 0.342

Gnomad4 FIN exome AF: 0.278

Gnomad4 NFE exome AF: 0.276

Gnomad4 OTH exome AF: 0.288

GnomAD4 genome AF: 0.286 AC: 43405 AN: 151918 Hom.: 6505 Cov.: 31 AF XY: 0.288 AC XY: 21363 AN XY: 74240

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.370

Gnomad4 ASJ AF: 0.225

Gnomad4 EAS AF: 0.473

Gnomad4 SAS AF: 0.349

Gnomad4 FIN AF: 0.271

Gnomad4 NFE AF: 0.275

Gnomad4 OTH AF: 0.286

Alfa AF: 0.269 Hom.: 5540

Bravo AF: 0.294

Asia WGS AF: 0.423 AC: 1467 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Ovarian dysgenesis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Ovarian hyperstimulation syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.89

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: rs1394205; hg19: chr2-49381585; COSMIC: COSV58618032; COSMIC: COSV58618032;