chr2-70785602-C-G

Position:

• chr2-70785602-C-G

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 336909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-70785602-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.888 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FIGLA	NM_001004311.3	c.422G>C	p.Ser141Thr	missense_variant	3/5	ENST00000332372.6	NP_001004311.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FIGLA	ENST00000332372.6	c.422G>C	p.Ser141Thr	missense_variant	3/5	1	NM_001004311.3	ENSP00000333097	P1

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

GnomAD3 exomes AF: 0.625 AC: 155849 AN: 249254 Hom.: 50556 AF XY: 0.616 AC XY: 83335 AN XY: 135220

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 SAS exome AF: 0.657

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

Gnomad4 AFR exome AF: 0.834

Gnomad4 AMR exome AF: 0.678

Gnomad4 ASJ exome AF: 0.527

Gnomad4 EAS exome AF: 0.916

Gnomad4 SAS exome AF: 0.648

Gnomad4 FIN exome AF: 0.630

Gnomad4 NFE exome AF: 0.530

Gnomad4 OTH exome AF: 0.590

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

Gnomad4 AFR AF: 0.821

Gnomad4 AMR AF: 0.649

Gnomad4 ASJ AF: 0.535

Gnomad4 EAS AF: 0.909

Gnomad4 SAS AF: 0.673

Gnomad4 FIN AF: 0.642

Gnomad4 NFE AF: 0.536

Gnomad4 OTH AF: 0.661

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Premature ovarian failure 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25314148) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	P
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

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: rs7566476; hg19: chr2-71012734; COSMIC: COSV60089132;