Variant chr4-121037201-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_024574.4(NDNF):c.770T>C(p.Phe257Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NDNF
NM_024574.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.29

Variant links:

Genes affected

NDNF (HGNC:26256): (neuron derived neurotrophic factor) Predicted to enable heparin binding activity. Involved in several processes, including cellular response to hypoxia; negative regulation of apoptotic process; and nitric oxide mediated signal transduction. Located in extracellular space. Implicated in hypogonadotropic hypogonadism. [provided by Alliance of Genome Resources, Apr 2022]

NDNF links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NDNF	NM_024574.4 linkuse as main transcript	c.770T>C	p.Phe257Ser	missense_variant	4/4	ENST00000379692.9
NDNF	XM_024454212.2 linkuse as main transcript	c.770T>C	p.Phe257Ser	missense_variant	4/4
NDNF	XM_024454213.2 linkuse as main transcript	c.770T>C	p.Phe257Ser	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDNF	ENST00000379692.9 linkuse as main transcript	c.770T>C	p.Phe257Ser	missense_variant	4/4	1	NM_024574.4	P1
NDNF	ENST00000506900.1 linkuse as main transcript	n.800T>C		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

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

Dec 02, 2022

The c.770T>C (p.F257S) alteration is located in exon 4 (coding exon 3) of the NDNF gene. This alteration results from a T to C substitution at nucleotide position 770, causing the phenylalanine (F) at amino acid position 257 to be replaced by a serine (S). 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

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.026

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

M_CAP

Benign

0.019

MetaRNN

Pathogenic

0.78

MetaSVM

Uncertain

-0.27

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.94

REVEL

Uncertain

0.30

Sift

Benign

0.078

Sift4G

Benign

0.28

Polyphen

1.0

Vest4

0.79

MutPred

0.21

Gain of phosphorylation at F257 (P = 0.0169);

MVP

0.61

MPC

0.55

ClinPred

0.87

GERP RS

5.9

Varity_R

0.33

gMVP

0.78

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