12-5494407-A-G

Position:

• chr12-5494407-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001102654.2(NTF3):​c.232A>G​(p.Lys78Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000055 (0 hom.)
• Consequence: NTF3 NM_001102654.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43

Genes affected

NTF3 (HGNC:8023): (neurotrophin 3) The protein encoded by this gene is a member of the neurotrophin family, that controls survival and differentiation of mammalian neurons. This protein is closely related to both nerve growth factor and brain-derived neurotrophic factor. It may be involved in the maintenance of the adult nervous system, and may affect development of neurons in the embryo when it is expressed in human placenta. NTF3-deficient mice generated by gene targeting display severe movement defects of the limbs. The mature peptide of this protein is identical in all mammals examined including human, pig, rat and mouse. [provided by RefSeq, Jul 2008]

NTF3 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18043515).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTF3	NM_001102654.2	c.232A>G	p.Lys78Glu	missense_variant	2/2	ENST00000423158.4	NP_001096124.1
NTF3	NM_002527.5	c.193A>G	p.Lys65Glu	missense_variant	1/1		NP_002518.1
NTF3	XM_011520963.3	c.193A>G	p.Lys65Glu	missense_variant	2/2		XP_011519265.1
NTF3	XM_047428901.1	c.193A>G	p.Lys65Glu	missense_variant	2/2		XP_047284857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTF3	ENST00000423158.4	c.232A>G	p.Lys78Glu	missense_variant	2/2	1	NM_001102654.2	ENSP00000397297.2
NTF3	ENST00000331010.7	c.193A>G	p.Lys65Glu	missense_variant	1/1	6		ENSP00000328738.6
NTF3	ENST00000543548.1	n.422A>G		non_coding_transcript_exon_variant	2/2	3
NTF3	ENST00000535299.5	n.232-12158A>G		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461576 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727114

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Oct 26, 2022

The c.193A>G (p.K65E) alteration is located in exon 1 (coding exon 1) of the NTF3 gene. This alteration results from a A to G substitution at nucleotide position 193, causing the lysine (K) at amino acid position 65 to be replaced by a glutamic acid (E). 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	0.061
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	.;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.048
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.26	T;T
Polyphen		0.0090	.;B
Vest4		0.26
MutPred		0.27		.;Loss of ubiquitination at K65 (P = 0.002);
MVP		0.40
MPC		2.2
ClinPred		0.75	D
GERP RS		3.6
Varity_R		0.21
gMVP		0.26

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: rs1940977642; hg19: chr12-5603573;