chr4-121037318-T-C
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_024574.4(NDNF):āc.653A>Gā(p.Glu218Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,614,148 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.00024 ( 0 hom., cov: 32)
Exomes š: 0.00030 ( 3 hom. )
Consequence
NDNF
NM_024574.4 missense
NM_024574.4 missense
Scores
1
9
9
Clinical Significance
Conservation
PhyloP100: 7.99
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.2939554).
BS2
High AC in GnomAd4 at 36 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDNF | NM_024574.4 | c.653A>G | p.Glu218Gly | missense_variant | 4/4 | ENST00000379692.9 | |
NDNF | XM_024454212.2 | c.653A>G | p.Glu218Gly | missense_variant | 4/4 | ||
NDNF | XM_024454213.2 | c.653A>G | p.Glu218Gly | missense_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDNF | ENST00000379692.9 | c.653A>G | p.Glu218Gly | missense_variant | 4/4 | 1 | NM_024574.4 | P1 | |
NDNF | ENST00000506900.1 | n.683A>G | non_coding_transcript_exon_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000237 AC: 36AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000320 AC: 80AN: 250288Hom.: 0 AF XY: 0.000361 AC XY: 49AN XY: 135672
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GnomAD4 exome AF: 0.000298 AC: 435AN: 1461884Hom.: 3 Cov.: 68 AF XY: 0.000323 AC XY: 235AN XY: 727244
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GnomAD4 genome AF: 0.000236 AC: 36AN: 152264Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74444
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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 | Jun 03, 2022 | The c.653A>G (p.E218G) alteration is located in exon 4 (coding exon 3) of the NDNF gene. This alteration results from a A to G substitution at nucleotide position 653, causing the glutamic acid (E) at amino acid position 218 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at