19-49061619-C-A

Variant names:

• chr19-49061619-C-A
• rs369484075
• NM_006179.5:c.379G>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_006179.5(NTF4):​c.379G>T​(p.Ala127Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NTF4 NM_006179.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.129

Genes affected

NTF4 (HGNC:8024): (neurotrophin 4) This gene is a member of a family of neurotrophic factors, neurotrophins, that control survival and differentiation of mammalian neurons. The expression of this gene is ubiquitous and less influenced by environmental signals. While knock-outs of other neurotrophins including nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 prove lethal during early postnatal development, NTF5-deficient mice only show minor cellular deficits and develop normally to adulthood. [provided by RefSeq, Jul 2008]

ENSG00000283663 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11017871).
• BS2: High AC in GnomAd4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTF4	NM_006179.5	c.379G>T	p.Ala127Ser	missense_variant	Exon 2 of 2	ENST00000593537.2	NP_006170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTF4	ENST00000593537.2	c.379G>T	p.Ala127Ser	missense_variant	Exon 2 of 2	6	NM_006179.5	ENSP00000469455.1
ENSG00000283663	ENST00000599795.5	n.243+136G>T		intron_variant	Intron 3 of 6	2		ENSP00000470689.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152276 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461568 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727084

Gnomad4 AFR exome AF: 0.0000896

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 AF: 0.0000394 AC: 6 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74398

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.379G>T (p.A127S) alteration is located in exon 2 (coding exon 1) of the NTF4 gene. This alteration results from a G to T substitution at nucleotide position 379, causing the alanine (A) at amino acid position 127 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	Benign	0.085
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.20	N;.
PrimateAI	Uncertain	0.50	T
Sift4G	Benign	0.86	T;.
Polyphen		0.0030	B;.
Vest4		0.14
MVP		0.42
ClinPred		0.79	D
GERP RS		2.1
Varity_R		0.13
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs369484075; hg19: chr19-49564876;