Genetic Variant NTF4:p.Gln174Pro (chr19-49061477-T-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_006179.5(NTF4):c.521A>C(p.Gln174Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q174R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NTF4
NM_006179.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.67

Publications

0 publications found

Variant links:

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]

NTF4 Gene-Disease associations (from GenCC):

glaucoma 1, open angle, O
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

NTF4 links:

ENSG00000283663 (HGNC:):

ENSG00000283663 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-49061477-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 208763.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.844

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006179.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTF4	NM_006179.5	MANE Select	c.521A>C	p.Gln174Pro	missense	Exon 2 of 2	NP_006170.1
	NTF4	NM_001395489.1		c.521A>C	p.Gln174Pro	missense	Exon 3 of 3	NP_001382418.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NTF4	ENST00000593537.2	TSL:6 MANE Select	c.521A>C	p.Gln174Pro	missense	Exon 2 of 2	ENSP00000469455.1
ENSG00000283663	ENST00000599795.5	TSL:2	n.243+278A>C		intron	N/A	ENSP00000470689.1
NTF4	ENST00000594938.2	TSL:5	c.521A>C	p.Gln174Pro	missense	Exon 3 of 3	ENSP00000512387.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461636

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111860

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.4

PhyloP100

2.7

PrimateAI

Uncertain

0.71

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.80

MutPred

0.69

Loss of MoRF binding (P = 0.0523)

MVP

0.79

ClinPred

0.95

GERP RS

3.3

Varity_R

0.73

gMVP

0.87

Mutation Taster

=34/66

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over