19-49061735-G-A

Position:

• chr19-49061735-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_006179.5(NTF4):​c.263C>T​(p.Ala88Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00334 in 1,611,310 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (38 hom.)
• Consequence: NTF4 NM_006179.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: 1.65

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 19-49061735-G-A is Benign according to our data. Variant chr19-49061735-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 14017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00253 (386/152332) while in subpopulation SAS AF= 0.0189 (91/4824). AF 95% confidence interval is 0.0157. There are 3 homozygotes in gnomad4. There are 196 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 386 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTF4	NM_006179.5	c.263C>T	p.Ala88Val	missense_variant	2/2	ENST00000593537.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTF4	ENST00000593537.2	c.263C>T	p.Ala88Val	missense_variant	2/2		NM_006179.5	P1

Frequencies

GnomAD3 genomes AF: 0.00255 AC: 388 AN: 152214 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00295

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00454 AC: 1093 AN: 240822 Hom.: 11 AF XY: 0.00536 AC XY: 705 AN XY: 131522

Gnomad AFR exome AF: 0.000476

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.00631

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0179

Gnomad FIN exome AF: 0.000532

Gnomad NFE exome AF: 0.00349

Gnomad OTH exome AF: 0.00556

GnomAD4 exome AF: 0.00343 AC: 4998 AN: 1458978 Hom.: 38 Cov.: 32 AF XY: 0.00391 AC XY: 2836 AN XY: 725736

Gnomad4 AFR exome AF: 0.000509

Gnomad4 AMR exome AF: 0.00169

Gnomad4 ASJ exome AF: 0.00633

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0178

Gnomad4 FIN exome AF: 0.000459

Gnomad4 NFE exome AF: 0.00256

Gnomad4 OTH exome AF: 0.00405

GnomAD4 genome AF: 0.00253 AC: 386 AN: 152332 Hom.: 3 Cov.: 32 AF XY: 0.00263 AC XY: 196 AN XY: 74492

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0189

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00295

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00344 Hom.: 3

Bravo AF: 0.00234

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000460 AC: 2

ESP6500EA AF: 0.00317 AC: 27

ExAC AF: 0.00469 AC: 567

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glaucoma 1, open angle, O Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Mar 12, 2010

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Intellectual disability, X-linked 99 Benign:1

Likely benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The heterozygous p.Ala88Val variant in NTF4 has been identified in at least 13 individuals with glaucoma and at least 19 individuals without glaucoma (PMID: 19765683, 20215012, 20463313), but has also been identified in >2% of South Asian chromosomes and 8 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant primary open angle glaucoma. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.022	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.69	N;.
MutationTaster	Benign	0.000059	A
PrimateAI	Uncertain	0.55	T
Sift4G	Benign	0.48	T;.
Polyphen		1.0	D;.
Vest4		0.32
MVP		0.78
ClinPred		0.030	T
GERP RS		3.5
Varity_R		0.11
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61732310; hg19: chr19-49564992; COSMIC: COSV56824972; COSMIC: COSV56824972;