NM_000145.4:c.919G>A

Variant names:

• chr2-48963902-C-T
• rs6165
• NM_000145.4:c.919G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000145.4(FSHR):​c.919G>A​(p.Ala307Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 1,613,318 control chromosomes in the GnomAD database, including 240,465 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18808 hom., cov: 31)
  • Exomes 𝑓: 0.55 (221657 hom.)
• Consequence: FSHR NM_000145.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0220
• Publications: 229 publications found

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

ENSG00000282890 (HGNC:58158):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: -0.79874 (below the threshold of 3.09). Trascript score misZ: -0.97417 (below the threshold of 3.09). GenCC associations: The gene is linked to ovarian hyperstimulation syndrome, ovarian dysgenesis 1, 46 XX gonadal dysgenesis.
• BP4: Computational evidence support a benign effect (MetaRNN=5.7555785E-6).
• BP6: Variant 2-48963902-C-T is Benign according to our data. Variant chr2-48963902-C-T is described in ClinVar as Benign. ClinVar VariationId is 16246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FSHR	NM_000145.4	c.919G>A	p.Ala307Thr	missense_variant	Exon 10 of 10	ENST00000406846.7	NP_000136.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FSHR	ENST00000406846.7	c.919G>A	p.Ala307Thr	missense_variant	Exon 10 of 10	1	NM_000145.4	ENSP00000384708.2
FSHR	ENST00000304421.8	c.841G>A	p.Ala281Thr	missense_variant	Exon 9 of 9	1		ENSP00000306780.4
FSHR	ENST00000454032.5	c.733G>A	p.Ala245Thr	missense_variant	Exon 9 of 9	1		ENSP00000415504.1
ENSG00000282890	ENST00000634588.1	n.492+17497C>T		intron_variant	Intron 2 of 4	5

Frequencies

GnomAD3 genomes AF: 0.480 AC: 72918 AN: 151824 Hom.: 18810 Cov.: 31

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.666

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.492

GnomAD2 exomes AF: 0.553 AC: 138761 AN: 250846 AF XY: 0.552

Gnomad AFR exome AF: 0.274

Gnomad AMR exome AF: 0.691

Gnomad ASJ exome AF: 0.468

Gnomad EAS exome AF: 0.651

Gnomad FIN exome AF: 0.555

Gnomad NFE exome AF: 0.547

Gnomad OTH exome AF: 0.556

GnomAD4 exome AF: 0.548 AC: 800618 AN: 1461376 Hom.: 221657 Cov.: 44 AF XY: 0.547 AC XY: 397799 AN XY: 727008

African (AFR) AF: 0.276 AC: 9241 AN: 33472

American (AMR) AF: 0.674 AC: 30166 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 12112 AN: 26132

East Asian (EAS) AF: 0.643 AC: 25512 AN: 39694

South Asian (SAS) AF: 0.534 AC: 46085 AN: 86244

European-Finnish (FIN) AF: 0.555 AC: 29629 AN: 53398

Middle Eastern (MID) AF: 0.481 AC: 2767 AN: 5748

European-Non Finnish (NFE) AF: 0.551 AC: 612715 AN: 1111582

Other (OTH) AF: 0.536 AC: 32391 AN: 60382

GnomAD4 genome AF: 0.480 AC: 72927 AN: 151942 Hom.: 18808 Cov.: 31 AF XY: 0.483 AC XY: 35853 AN XY: 74230

African (AFR) AF: 0.281 AC: 11629 AN: 41446

American (AMR) AF: 0.582 AC: 8879 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1636 AN: 3468

East Asian (EAS) AF: 0.666 AC: 3432 AN: 5156

South Asian (SAS) AF: 0.550 AC: 2643 AN: 4802

European-Finnish (FIN) AF: 0.552 AC: 5831 AN: 10554

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.549 AC: 37275 AN: 67948

Other (OTH) AF: 0.488 AC: 1031 AN: 2112

Alfa AF: 0.523 Hom.: 68423

Bravo AF: 0.476

TwinsUK AF: 0.551 AC: 2042

ALSPAC AF: 0.550 AC: 2119

ESP6500AA AF: 0.285 AC: 1256

ESP6500EA AF: 0.542 AC: 4657

ExAC AF: 0.544 AC: 66106

Asia WGS AF: 0.562 AC: 1953 AN: 3478

EpiCase AF: 0.538

EpiControl AF: 0.540

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ovarian dysgenesis 1 Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28547204, 26291798, 16574671, 23139742, 20399696, 18591890, 23536150, 18321487, 19550076) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.69
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.55	T;.;T
MetaRNN	Benign	0.0000058	T;T;T
MetaSVM	Benign	-0.93	T
PhyloP100		0.022
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.070	N;N;N
REVEL	Benign	0.049
Sift	Benign	0.45	T;T;T
Sift4G	Benign	0.64	T;T;.
Vest4		0.029
MPC		0.023
ClinPred		0.0080	T
GERP RS		1.8
gMVP		0.56
Mutation Taster		=88/12	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6165; hg19: chr2-49191041; COSMIC: COSV58617865; COSMIC: COSV58617865;