chr12-5494441-G-A

Position:

• chr12-5494441-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001102654.2(NTF3):​c.266G>A​(p.Gly89Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0272 in 1,612,718 control chromosomes in the GnomAD database, including 4,527 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G89R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.080 (1149 hom., cov: 31)
  • Exomes 𝑓: 0.022 (3378 hom.)
• Consequence: NTF3 NM_001102654.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.88

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003197819).
• BP6: Variant 12-5494441-G-A is Benign according to our data. Variant chr12-5494441-G-A is described in ClinVar as [Benign]. Clinvar id is 599416.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTF3	NM_001102654.2	c.266G>A	p.Gly89Glu	missense_variant	2/2	ENST00000423158.4
NTF3	NM_002527.5	c.227G>A	p.Gly76Glu	missense_variant	1/1
NTF3	XM_011520963.3	c.227G>A	p.Gly76Glu	missense_variant	2/2
NTF3	XM_047428901.1	c.227G>A	p.Gly76Glu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTF3	ENST00000423158.4	c.266G>A	p.Gly89Glu	missense_variant	2/2	1	NM_001102654.2	P4
NTF3	ENST00000331010.7	c.227G>A	p.Gly76Glu	missense_variant	1/1			A1
NTF3	ENST00000543548.1	n.456G>A		non_coding_transcript_exon_variant	2/2	3
NTF3	ENST00000535299.5	n.232-12124G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0796 AC: 12087 AN: 151776 Hom.: 1139 Cov.: 31

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.0338

Gnomad FIN AF: 0.00755

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.0668

GnomAD3 exomes AF: 0.0689 AC: 17118 AN: 248484 Hom.: 2135 AF XY: 0.0539 AC XY: 7268 AN XY: 134792

Gnomad AFR exome AF: 0.204

Gnomad AMR exome AF: 0.281

Gnomad ASJ exome AF: 0.00309

Gnomad EAS exome AF: 0.149

Gnomad SAS exome AF: 0.0249

Gnomad FIN exome AF: 0.00875

Gnomad NFE exome AF: 0.00206

Gnomad OTH exome AF: 0.0430

GnomAD4 exome AF: 0.0218 AC: 31810 AN: 1460824 Hom.: 3378 Cov.: 31 AF XY: 0.0198 AC XY: 14385 AN XY: 726784

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.271

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.175

Gnomad4 SAS exome AF: 0.0251

Gnomad4 FIN exome AF: 0.00801

Gnomad4 NFE exome AF: 0.00115

Gnomad4 OTH exome AF: 0.0328

GnomAD4 genome AF: 0.0799 AC: 12135 AN: 151894 Hom.: 1149 Cov.: 31 AF XY: 0.0819 AC XY: 6078 AN XY: 74232

Gnomad4 AFR AF: 0.193

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.159

Gnomad4 SAS AF: 0.0341

Gnomad4 FIN AF: 0.00755

Gnomad4 NFE AF: 0.00227

Gnomad4 OTH AF: 0.0680

Alfa AF: 0.0192 Hom.: 491

Bravo AF: 0.102

ESP6500AA AF: 0.186 AC: 819

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.0613 AC: 7437

Asia WGS AF: 0.107 AC: 371 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00142

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Aganglionic megacolon Benign:1

Likely benign, no assertion criteria provided

research

Human Genomics Unit, Institute for molecular medicine Finland (FIMM)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.7
DANN	Benign	0.47
DEOGEN2	Benign	0.26	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.28	T;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.9	.;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.61	N;N
REVEL	Benign	0.065
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.018
MPC		1.1
ClinPred		0.0014	T
GERP RS		4.8
Varity_R		0.029
gMVP		0.084

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: rs1805149; hg19: chr12-5603607;