rs7566476

Variant names:

• chr2-70785602-C-G
• rs7566476
• NM_001004311.3:c.422G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001004311.3(FIGLA):​c.422G>C​(p.Ser141Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 1,613,180 control chromosomes in the GnomAD database, including 273,140 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33588 hom., cov: 32)
  • Exomes 𝑓: 0.57 (239552 hom.)
• Consequence: FIGLA NM_001004311.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.52
• Publications: 26 publications found

Genes affected

FIGLA (HGNC:24669): (folliculogenesis specific bHLH transcription factor) This gene encodes a protein that functions in postnatal oocyte-specific gene expression. The protein is a basic helix-loop-helix transcription factor that regulates multiple oocyte-specific genes, including genes involved in folliculogenesis and those that encode the zona pellucida. Mutations in this gene cause premature ovarian failure type 6. [provided by RefSeq, Sep 2009]

FIGLA Gene-Disease associations (from GenCC):

• premature ovarian failure 6

  Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.066784E-7).
• BP6: Variant 2-70785602-C-G is Benign according to our data. Variant chr2-70785602-C-G is described in ClinVar as Benign. ClinVar VariationId is 336909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.888 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004311.3. 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
	FIGLA	NM_001004311.3	MANE Select	c.422G>C	p.Ser141Thr	missense	Exon 3 of 5	NP_001004311.2	Q6QHK4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIGLA	ENST00000332372.6	TSL:1 MANE Select	c.422G>C	p.Ser141Thr	missense	Exon 3 of 5	ENSP00000333097.6	Q6QHK4

Frequencies

GnomAD3 genomes AF: 0.652 AC: 99033 AN: 151978 Hom.: 33545 Cov.: 32

Gnomad AFR AF: 0.821

Gnomad AMI AF: 0.619

Gnomad AMR AF: 0.648

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.909

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.642

Gnomad MID AF: 0.580

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.658

GnomAD2 exomes AF: 0.625 AC: 155849 AN: 249254 AF XY: 0.616

Gnomad AFR exome AF: 0.827

Gnomad AMR exome AF: 0.684

Gnomad ASJ exome AF: 0.531

Gnomad EAS exome AF: 0.910

Gnomad FIN exome AF: 0.631

Gnomad NFE exome AF: 0.535

Gnomad OTH exome AF: 0.592

GnomAD4 exome AF: 0.565 AC: 825835 AN: 1461084 Hom.: 239552 Cov.: 47 AF XY: 0.566 AC XY: 411306 AN XY: 726838

African (AFR) AF: 0.834 AC: 27915 AN: 33476

American (AMR) AF: 0.678 AC: 30330 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 13764 AN: 26136

East Asian (EAS) AF: 0.916 AC: 36381 AN: 39700

South Asian (SAS) AF: 0.648 AC: 55902 AN: 86236

European-Finnish (FIN) AF: 0.630 AC: 33626 AN: 53400

Middle Eastern (MID) AF: 0.615 AC: 3545 AN: 5764

European-Non Finnish (NFE) AF: 0.530 AC: 588794 AN: 1111302

Other (OTH) AF: 0.590 AC: 35578 AN: 60346

GnomAD4 genome AF: 0.652 AC: 99138 AN: 152096 Hom.: 33588 Cov.: 32 AF XY: 0.659 AC XY: 48983 AN XY: 74350

African (AFR) AF: 0.821 AC: 34074 AN: 41508

American (AMR) AF: 0.649 AC: 9905 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 1854 AN: 3468

East Asian (EAS) AF: 0.909 AC: 4714 AN: 5184

South Asian (SAS) AF: 0.673 AC: 3243 AN: 4820

European-Finnish (FIN) AF: 0.642 AC: 6784 AN: 10566

Middle Eastern (MID) AF: 0.579 AC: 169 AN: 292

European-Non Finnish (NFE) AF: 0.536 AC: 36437 AN: 67970

Other (OTH) AF: 0.661 AC: 1395 AN: 2112

Alfa AF: 0.561 Hom.: 18542

Bravo AF: 0.664

TwinsUK AF: 0.529 AC: 1960

ALSPAC AF: 0.530 AC: 2041

ESP6500AA AF: 0.814 AC: 3225

ESP6500EA AF: 0.538 AC: 4492

ExAC AF: 0.623 AC: 75295

Asia WGS AF: 0.782 AC: 2720 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Premature ovarian failure 6 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	6.9
DANN	Benign	0.51
DEOGEN2	Benign	0.077	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	7.1e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.2	N
PhyloP100		1.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.66	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.017
MPC		0.081
ClinPred		0.011	T
GERP RS		3.2
Varity_R		0.047
gMVP		0.20
Mutation Taster		=100/0	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: rs7566476; hg19: chr2-71012734; COSMIC: COSV60089132;