chr3-138950337-A-G

Position:

• chr3-138950337-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001040061.3(FOXL2NB):​c.293A>G​(p.Lys98Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FOXL2NB NM_001040061.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

Genes affected

FOXL2NB (HGNC:34428): (FOXL2 neighbor) Located in fibrillar center. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03723076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXL2NB	NM_001040061.3	c.293A>G	p.Lys98Arg	missense_variant	3/3	ENST00000383165.4	NP_001035150.1
FOXL2NB	XM_005247443.4	c.224A>G	p.Lys75Arg	missense_variant	4/4		XP_005247500.1
FOXL2NB	XM_024453517.2	c.*94A>G		3_prime_UTR_variant	2/2		XP_024309285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXL2NB	ENST00000383165.4	c.293A>G	p.Lys98Arg	missense_variant	3/3	2	NM_001040061.3	ENSP00000372651	P1
FOXL2NB	ENST00000498709.1	n.1222A>G		non_coding_transcript_exon_variant	2/2	2
FOXL2NB	ENST00000470680.5	c.*175A>G		3_prime_UTR_variant, NMD_transcript_variant	3/3	3		ENSP00000418272

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000419 AC: 1 AN: 238654 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 131240

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: 0.00000933

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000834 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2024

The c.293A>G (p.K98R) alteration is located in exon 3 (coding exon 3) of the FOXL2NB gene. This alteration results from a A to G substitution at nucleotide position 293, causing the lysine (K) at amino acid position 98 to be replaced by an arginine (R). 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	0.089
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.49
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.11	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.042
MutPred		0.14		Gain of glycosylation at S103 (P = 0.0172);
MVP		0.030
MPC		0.47
ClinPred		0.048	T
GERP RS		-0.036
Varity_R		0.037
gMVP		0.012

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: rs762966600; hg19: chr3-138669179;