Genetic Variant ENST00000419927.1:n.-29G>A (chr2-49154556-G-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000419927.1(FSHR):n.-139C>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. 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 0.000015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000049 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FSHR
ENST00000419927.1 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0740

Publications

0 publications found

Variant links:

Genes affected

ENSG00000282890 (HGNC:58158):

ENSG00000282890 links:

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
FSHR	NM_000145.4 link	c.-139C>A	upstream_gene_variant	ENST00000406846.7	NP_000136.2
FSHR	NM_181446.3 link	c.-139C>A	upstream_gene_variant		NP_852111.2
FSHR	XM_011532733.3 link	c.-139C>A	upstream_gene_variant		XP_011531035.1
FSHR	XM_011532740.1 link	c.-139C>A	upstream_gene_variant		XP_011531042.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FSHR	ENST00000406846.7 link	c.-139C>A		upstream_gene_variant		1	NM_000145.4	ENSP00000384708.2

Frequencies

GnomAD3 genomes

AF:

0.0000151

AC:

AN:

132618

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000251

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000486

AC:

AN:

535304

Hom.:

Cov.:

AF XY:

0.0000601

AC XY:

AN XY:

282826

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000156

AC:

AN:

12838

American (AMR)

AF:

0.0000496

AC:

AN:

20180

Ashkenazi Jewish (ASJ)

AF:

0.0000685

AC:

AN:

14598

East Asian (EAS)

AF:

0.00

AC:

AN:

28854

South Asian (SAS)

AF:

0.0000822

AC:

AN:

48650

European-Finnish (FIN)

AF:

0.0000693

AC:

AN:

28872

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2060

European-Non Finnish (NFE)

AF:

0.0000398

AC:

AN:

351726

Other (OTH)

AF:

0.0000727

AC:

AN:

27526

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.252

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000151

AC:

AN:

132604

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

63960

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

35458

American (AMR)

AF:

0.00

AC:

AN:

12510

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3268

East Asian (EAS)

AF:

0.00

AC:

AN:

4012

South Asian (SAS)

AF:

0.00

AC:

AN:

3910

European-Finnish (FIN)

AF:

0.000251

AC:

AN:

7954

Middle Eastern (MID)

AF:

0.00

AC:

AN:

260

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

62568

Other (OTH)

AF:

0.00

AC:

AN:

1834

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.66

(source)

DANN

Benign

0.41

PhyloP100

0.074

PromoterAI

0.052

Neutral

(source)

Splicing

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

Computational scores

Splicing

Publications

Other links and lift over