rs6166

Variant names:

• chr2-48962782-C-T
• rs6166
• NM_000145.4:c.2039G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-48962782-C-T
• chr2-48962782-C-A
• chr2-48962782-C-G

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.2039G>A​(p.Ser680Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 1,613,272 control chromosomes in the GnomAD database, including 252,236 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 0.57 (24652 hom., cov: 32)
  • Exomes 𝑓: 0.56 (227584 hom.)
• Consequence: FSHR NM_000145.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0530
• Publications: 379 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

MIR548BAHG (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=6.0149523E-6).
• BP6: Variant 2-48962782-C-T is Benign according to our data. Variant chr2-48962782-C-T is described in ClinVar as Benign. ClinVar VariationId is 16247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000145.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FSHR	NM_000145.4	MANE Select	c.2039G>A	p.Ser680Asn	missense	Exon 10 of 10	NP_000136.2
	FSHR	NM_181446.3		c.1961G>A	p.Ser654Asn	missense	Exon 9 of 9	NP_852111.2	P23945-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FSHR	ENST00000406846.7	TSL:1 MANE Select	c.2039G>A	p.Ser680Asn	missense	Exon 10 of 10	ENSP00000384708.2	P23945-1
	FSHR	ENST00000304421.8	TSL:1	c.1961G>A	p.Ser654Asn	missense	Exon 9 of 9	ENSP00000306780.4	P23945-3
	MIR548BAHG	ENST00000634588.1	TSL:5	n.492+16377C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.568 AC: 86242 AN: 151908 Hom.: 24645 Cov.: 32

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.551

Gnomad OTH AF: 0.556

GnomAD2 exomes AF: 0.574 AC: 144230 AN: 251060 AF XY: 0.569

Gnomad AFR exome AF: 0.592

Gnomad AMR exome AF: 0.671

Gnomad ASJ exome AF: 0.476

Gnomad EAS exome AF: 0.669

Gnomad FIN exome AF: 0.556

Gnomad NFE exome AF: 0.548

Gnomad OTH exome AF: 0.566

GnomAD4 exome AF: 0.557 AC: 813884 AN: 1461246 Hom.: 227584 Cov.: 48 AF XY: 0.555 AC XY: 403744 AN XY: 726958

African (AFR) AF: 0.589 AC: 19699 AN: 33468

American (AMR) AF: 0.659 AC: 29452 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 12314 AN: 26134

East Asian (EAS) AF: 0.656 AC: 26024 AN: 39688

South Asian (SAS) AF: 0.542 AC: 46739 AN: 86254

European-Finnish (FIN) AF: 0.555 AC: 29661 AN: 53418

Middle Eastern (MID) AF: 0.510 AC: 2939 AN: 5764

European-Non Finnish (NFE) AF: 0.552 AC: 613307 AN: 1111428

Other (OTH) AF: 0.559 AC: 33749 AN: 60380

GnomAD4 genome AF: 0.568 AC: 86292 AN: 152026 Hom.: 24652 Cov.: 32 AF XY: 0.567 AC XY: 42132 AN XY: 74322

African (AFR) AF: 0.583 AC: 24186 AN: 41456

American (AMR) AF: 0.602 AC: 9197 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 1668 AN: 3466

East Asian (EAS) AF: 0.679 AC: 3514 AN: 5172

South Asian (SAS) AF: 0.561 AC: 2701 AN: 4818

European-Finnish (FIN) AF: 0.552 AC: 5828 AN: 10552

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.550 AC: 37415 AN: 67966

Other (OTH) AF: 0.554 AC: 1169 AN: 2112

Alfa AF: 0.556 Hom.: 108435

Bravo AF: 0.574

TwinsUK AF: 0.550 AC: 2040

ALSPAC AF: 0.551 AC: 2125

ESP6500AA AF: 0.587 AC: 2588

ESP6500EA AF: 0.543 AC: 4672

ExAC AF: 0.573 AC: 69519

Asia WGS AF: 0.588 AC: 2045 AN: 3478

EpiCase AF: 0.540

EpiControl AF: 0.543

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Ovarian hyperstimulation syndrome (3)
-	-	2	not provided (2)
-	-	2	Ovarian dysgenesis 1 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.29
DANN	Benign	0.18
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.0068	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0000060	T
MetaSVM	Benign	-0.92	T
PhyloP100		0.053
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.033
Sift	Benign	0.97	T
Sift4G	Benign	0.71	T
Vest4		0.013
MPC		0.023
ClinPred		0.0012	T
GERP RS		1.5
gMVP		0.30
Mutation Taster		=99/1	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: rs6166; hg19: chr2-49189921; COSMIC: COSV58619885; COSMIC: COSV58619885;