19-49061841-G-A

Variant names:

• chr19-49061841-G-A
• rs1017274820
• NM_006179.5:c.157C>T

Variant summary

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

The NM_006179.5(NTF4):​c.157C>T​(p.Pro53Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,398,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: NTF4 NM_006179.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.798

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22986528).
• BS2: High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTF4	NM_006179.5	c.157C>T	p.Pro53Ser	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.157C>T	p.Pro53Ser	missense_variant	Exon 2 of 2	6	NM_006179.5	ENSP00000469455.1
ENSG00000283663	ENST00000599795.5	n.157C>T		non_coding_transcript_exon_variant	Exon 3 of 7	2		ENSP00000470689.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000134 AC: 2 AN: 148966 Hom.: 0 AF XY: 0.0000251 AC XY: 2 AN XY: 79774

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: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 22 AN: 1398420 Hom.: 0 Cov.: 32 AF XY: 0.0000188 AC XY: 13 AN XY: 689878

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: 0.0000204

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.157C>T (p.P53S) alteration is located in exon 2 (coding exon 1) of the NTF4 gene. This alteration results from a C to T substitution at nucleotide position 157, causing the proline (P) at amino acid position 53 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	Uncertain	0.50
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Benign	-0.023
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.61	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.97	L;.
PrimateAI	Uncertain	0.61	T
Sift4G	Uncertain	0.0020	D;.
Polyphen		0.99	D;.
Vest4		0.25
MutPred		0.34		Gain of phosphorylation at P53 (P = 0.0233);Gain of phosphorylation at P53 (P = 0.0233);
MVP		0.77
ClinPred		0.27	T
GERP RS		2.6
Varity_R		0.18
gMVP		0.68

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: rs1017274820; hg19: chr19-49565098;