2-49154446-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000419927.1(FSHR):n.-29G>A variant causes a non coding transcript exon 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
ENST00000419927.1 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.730

Publications

102 publications found

Variant links:

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

FSHR links:

ENSG00000282890 (HGNC:58158):

ENSG00000282890 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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	Effect	Exon rank	MANE	Protein
FSHR	NM_000145.4 link	c.-29G>A	5_prime_UTR_variant	Exon 1 of 10	ENST00000406846.7	NP_000136.2
FSHR	NM_181446.3 link	c.-29G>A	5_prime_UTR_variant	Exon 1 of 9		NP_852111.2
FSHR	XM_011532733.3 link	c.-29G>A	5_prime_UTR_variant	Exon 1 of 11		XP_011531035.1
FSHR	XM_011532740.1 link	c.-29G>A	5_prime_UTR_variant	Exon 1 of 11		XP_011531042.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FSHR	ENST00000406846.7 link	c.-29G>A		5_prime_UTR_variant	Exon 1 of 10	1	NM_000145.4	ENSP00000384708.2

Frequencies

GnomAD3 genomes

AF:

0.286

AC:

43353

AN:

151800

Hom.:

6493

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.322

AC:

80116

AN:

249064

AF XY:

0.315

show subpopulations

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 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.:

AF XY:

0.291

AC XY:

210771

AN XY:

725280

show subpopulations

African (AFR)

AF:

0.248

AC:

8279

AN:

33378

American (AMR)

AF:

0.473

AC:

21107

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.216

AC:

5645

AN:

26110

East Asian (EAS)

AF:

0.480

AC:

19040

AN:

39664

South Asian (SAS)

AF:

0.342

AC:

29445

AN:

86122

European-Finnish (FIN)

AF:

0.278

AC:

14835

AN:

53340

Middle Eastern (MID)

AF:

0.255

AC:

1059

AN:

4158

European-Non Finnish (NFE)

AF:

0.276

AC:

305882

AN:

1110274

Other (OTH)

AF:

0.288

AC:

17328

AN:

60138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

14024

28048

42071

56095

70119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10468

20936

31404

41872

52340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.286

AC:

43405

AN:

151918

Hom.:

6505

Cov.:

AF XY:

0.288

AC XY:

21363

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.252

AC:

10425

AN:

41440

American (AMR)

AF:

0.370

AC:

5642

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.225

AC:

780

AN:

3468

East Asian (EAS)

AF:

0.473

AC:

2430

AN:

5140

South Asian (SAS)

AF:

0.349

AC:

1678

AN:

4808

European-Finnish (FIN)

AF:

0.271

AC:

2857

AN:

10554

Middle Eastern (MID)

AF:

0.197

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.275

AC:

18682

AN:

67934

Other (OTH)

AF:

0.286

AC:

603

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1573

3145

4718

6290

7863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

450

900

1350

1800

2250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.273

Hom.:

7336

Bravo

AF:

0.294

Asia WGS

AF:

0.423

AC:

1467

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 20, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ovarian dysgenesis 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

0.73

PromoterAI

-0.018

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over