chr2-48968881-T-A

Variant names:

• chr2-48968881-T-A
• rs386833515
• NM_000145.4:c.671A>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000145.4(FSHR):​c.671A>T​(p.Asp224Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FSHR NM_000145.4 missense, splice_region
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02
• Publications: 19 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000145.4
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 2-48968881-T-A is Pathogenic according to our data. Variant chr2-48968881-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 56034.Status of the report is no_assertion_criteria_provided, 0 stars.

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.671A>T	p.Asp224Val	missense splice_region	Exon 9 of 10	NP_000136.2
	FSHR	NM_181446.3		c.593A>T	p.Asp198Val	missense splice_region	Exon 8 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.671A>T	p.Asp224Val	missense splice_region	Exon 9 of 10	ENSP00000384708.2	P23945-1
	FSHR	ENST00000304421.8	TSL:1	c.593A>T	p.Asp198Val	missense splice_region	Exon 8 of 9	ENSP00000306780.4	P23945-3
	FSHR	ENST00000454032.5	TSL:1	c.669-4915A>T		intron	N/A	ENSP00000415504.1	C9JDA1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Ovarian dysgenesis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.045	D
PhyloP100		8.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.94
MutPred		0.78		Loss of phosphorylation at S226 (P = 0.1553)
MVP		0.98
MPC		0.22
ClinPred		1.0	D
GERP RS		5.5
gMVP		0.94
Mutation Taster		=18/82	disease causing (ClinVar)

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: rs386833515; hg19: chr2-49196020;