2-48963249-G-T

Position:

• chr2-48963249-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000145.4(FSHR):​c.1572C>A​(p.Ser524Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. S524S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FSHR NM_000145.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.480

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21554455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FSHR	NM_000145.4	c.1572C>A	p.Ser524Arg	missense_variant	10/10	ENST00000406846.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FSHR	ENST00000406846.7	c.1572C>A	p.Ser524Arg	missense_variant	10/10	1	NM_000145.4	P1
FSHR	ENST00000304421.8	c.1494C>A	p.Ser498Arg	missense_variant	9/9	1
	ENST00000634588.1	n.492+16844G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250686 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135448

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461822 Hom.: 0 Cov.: 43 AF XY: 0.00000413 AC XY: 3 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	0.078
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	D;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	0.63	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Vest4		0.19
MutPred		0.59		Gain of helix (P = 0.2294);.;
MVP		0.63
MPC		0.032
ClinPred		0.60	D
GERP RS		2.6
gMVP		0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs6167; hg19: chr2-49190388;