NM_001004311.3:c.646C>T

Variant names:

• chr2-70777381-G-A
• rs1490604836
• NM_001004311.3:c.646C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001004311.3(FIGLA):​c.646C>T​(p.Leu216Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000047 in 1,488,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: FIGLA NM_001004311.3 missense, splice_region
• Scores: Splicing: ADA: 0.00008493
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0240
• Publications: 0 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: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03949523).
• BS2: High AC in GnomAdExome4 at 5 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FIGLA	NM_001004311.3	c.646C>T	p.Leu216Phe	missense_variant, splice_region_variant	Exon 5 of 5	ENST00000332372.6	NP_001004311.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FIGLA	ENST00000332372.6	c.646C>T	p.Leu216Phe	missense_variant, splice_region_variant	Exon 5 of 5	1	NM_001004311.3	ENSP00000333097.6

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151672 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 132552 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000374 AC: 5 AN: 1336778 Hom.: 0 Cov.: 25 AF XY: 0.00000758 AC XY: 5 AN XY: 659866

African (AFR) AF: 0.00 AC: 0 AN: 29434

American (AMR) AF: 0.00 AC: 0 AN: 24988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23604

East Asian (EAS) AF: 0.00 AC: 0 AN: 35068

South Asian (SAS) AF: 0.00 AC: 0 AN: 67556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5424

European-Non Finnish (NFE) AF: 0.00000477 AC: 5 AN: 1047132

Other (OTH) AF: 0.00 AC: 0 AN: 55314

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151672 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74046

African (AFR) AF: 0.00 AC: 0 AN: 41286

American (AMR) AF: 0.00 AC: 0 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.646C>T (p.L216F) alteration is located in exon 5 (coding exon 5) of the FIGLA gene. This alteration results from a C to T substitution at nucleotide position 646, causing the leucine (L) at amino acid position 216 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.039	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.024
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.19
Sift	Benign	0.24	T
Sift4G	Benign	0.42	T
Polyphen		0.0020	B
Vest4		0.13
MutPred		0.12		Loss of stability (P = 0.0672);
MVP		0.18
MPC		0.097
ClinPred		0.075	T
GERP RS		-0.70
Varity_R		0.073
gMVP		0.060
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000085
dbscSNV1_RF	Benign	0.0
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: rs1490604836; hg19: chr2-71004513;