Variant 12-109281736-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_213596.3(FOXN4):c.965A>G(p.Glu322Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FOXN4
NM_213596.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.54

Variant links:

Genes affected

FOXN4 (HGNC:21399): (forkhead box N4) Members of the winged-helix/forkhead family of transcription factors, such as FOXN4, are characterized by a 110-amino acid DNA-binding domain that can fold into a variant of the helix-turn-helix motif consisting of 3 alpha helices flanked by 2 large loops or wings. These transcription factors are involved in a variety of biologic processes as key regulators in development and metabolism (Li et al., 2004 [PubMed 15363391]).[supplied by OMIM, Mar 2008]

FOXN4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3519981).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXN4	NM_213596.3 linkuse as main transcript	c.965A>G	p.Glu322Gly	missense_variant	9/10	ENST00000299162.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXN4	ENST00000299162.10 linkuse as main transcript	c.965A>G	p.Glu322Gly	missense_variant	9/10	1	NM_213596.3	P1	Q96NZ1-1
FOXN4	ENST00000423960.1 linkuse as main transcript	c.*63A>G		3_prime_UTR_variant, NMD_transcript_variant	6/7	1
FOXN4	ENST00000355216.5 linkuse as main transcript	c.425A>G	p.Glu142Gly	missense_variant	5/6	2			Q96NZ1-3
FOXN4	ENST00000468516.1 linkuse as main transcript	c.143-2307A>G		intron_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000416

AC:

AN:

240148

Hom.:

AF XY:

0.00000763

AC XY:

AN XY:

131064

show subpopulations

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:

0.00000935

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1454890

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722906

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.965A>G (p.E322G) alteration is located in exon 9 (coding exon 8) of the FOXN4 gene. This alteration results from a A to G substitution at nucleotide position 965, causing the glutamic acid (E) at amino acid position 322 to be replaced by a glycine (G). 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

0.083

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.083

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.046

MetaRNN

Benign

0.35

T;T

MetaSVM

Uncertain

0.35

MutationTaster

Benign

0.97

D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.23

Sift

Benign

0.12

T;T

Sift4G

Benign

0.32

T;T

Polyphen

0.0

.;B

Vest4

0.47

MutPred

0.35

.;Gain of catalytic residue at E322 (P = 9e-04);

MVP

0.96

MPC

0.25

ClinPred

0.32

GERP RS

4.7

Varity_R

0.18

gMVP

0.37

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over