12-5494901-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001102654.2(NTF3):c.726A>G(p.Ser242=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,614,208 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0057 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (7 hom.)
• Consequence: NTF3 NM_001102654.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.165

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 12-5494901-A-G is Benign according to our data. Variant chr12-5494901-A-G is described in ClinVar as [Benign]. Clinvar id is 784229.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.165 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00572 (871/152332) while in subpopulation AFR AF= 0.0185 (767/41562). AF 95% confidence interval is 0.0174. There are 8 homozygotes in gnomad4. There are 404 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 870 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTF3	NM_001102654.2	c.726A>G	p.Ser242=	synonymous_variant	2/2	ENST00000423158.4
NTF3	NM_002527.5	c.687A>G	p.Ser229=	synonymous_variant	1/1
NTF3	XM_011520963.3	c.687A>G	p.Ser229=	synonymous_variant	2/2
NTF3	XM_047428901.1	c.687A>G	p.Ser229=	synonymous_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTF3	ENST00000423158.4	c.726A>G	p.Ser242=	synonymous_variant	2/2	1	NM_001102654.2	P4
NTF3	ENST00000331010.7	c.687A>G	p.Ser229=	synonymous_variant	1/1			A1
NTF3	ENST00000535299.5	n.232-11664A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00572 AC: 870 AN: 152214 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00189 AC: 475 AN: 251424 Hom.: 4 AF XY: 0.00153 AC XY: 208 AN XY: 135904

Gnomad AFR exome AF: 0.0184

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00744

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000869 AC: 1270 AN: 1461876 Hom.: 7 Cov.: 33 AF XY: 0.000770 AC XY: 560 AN XY: 727242

Gnomad4 AFR exome AF: 0.0178

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.00746

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000237

Gnomad4 OTH exome AF: 0.00204

GnomAD4 genome AF: 0.00572 AC: 871 AN: 152332 Hom.: 8 Cov.: 32 AF XY: 0.00542 AC XY: 404 AN XY: 74496

Gnomad4 AFR AF: 0.0185

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00329 Hom.: 4

Bravo AF: 0.00617

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 13, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	6.6
Dann	Benign	0.58

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: rs71532853; hg19: chr12-5604067;