Genetic Variant NM_000145.4:c.153-11T>A (chr2-49068301-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000145.4(FSHR):c.153-11T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FSHR
NM_000145.4 intron

Scores

Splicing: ADA: 0.8434

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.74

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
FSHR	NM_000145.4 link	c.153-11T>A	intron_variant	Intron 1 of 9	ENST00000406846.7	NP_000136.2
FSHR	NM_181446.3 link	c.153-11T>A	intron_variant	Intron 1 of 8		NP_852111.2
FSHR	XM_011532733.3 link	c.153-11T>A	intron_variant	Intron 1 of 10		XP_011531035.1
FSHR	XM_011532740.1 link	c.153-11T>A	intron_variant	Intron 1 of 10		XP_011531042.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FSHR	ENST00000406846.7 link	c.153-11T>A		intron_variant	Intron 1 of 9	1	NM_000145.4	ENSP00000384708.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455860

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724648

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33312

American (AMR)

AF:

0.00

AC:

AN:

44612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26020

East Asian (EAS)

AF:

0.00

AC:

AN:

39640

South Asian (SAS)

AF:

0.00

AC:

AN:

86150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53118

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107122

Other (OTH)

AF:

0.00

AC:

AN:

60144

⚠️ 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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Amenorrhea

Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

2.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.84

dbscSNV1_RF

Benign

0.68

SpliceAI score (max)

0.70

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.70

Position offset: -11

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over