chr12-5494572-A-C

Variant names:

• chr12-5494572-A-C
• rs1022358940
• NM_001102654.2:c.397A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001102654.2(NTF3):​c.397A>C​(p.Met133Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NTF3 NM_001102654.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13848239).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTF3	NM_001102654.2	c.397A>C	p.Met133Leu	missense_variant	Exon 2 of 2	ENST00000423158.4	NP_001096124.1
NTF3	NM_002527.5	c.358A>C	p.Met120Leu	missense_variant	Exon 1 of 1		NP_002518.1
NTF3	XM_011520963.3	c.358A>C	p.Met120Leu	missense_variant	Exon 2 of 2		XP_011519265.1
NTF3	XM_047428901.1	c.358A>C	p.Met120Leu	missense_variant	Exon 2 of 2		XP_047284857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTF3	ENST00000423158.4	c.397A>C	p.Met133Leu	missense_variant	Exon 2 of 2	1	NM_001102654.2	ENSP00000397297.2
NTF3	ENST00000331010.7	c.358A>C	p.Met120Leu	missense_variant	Exon 1 of 1	6		ENSP00000328738.6
NTF3	ENST00000535299.5	n.232-11993A>C		intron_variant	Intron 1 of 4	5
NTF3	ENST00000543548.1	n.*71A>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151950 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000154 AC: 224 AN: 1455628 Hom.: 0 Cov.: 36 AF XY: 0.000141 AC XY: 102 AN XY: 724348

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000120 AC: 4 AN: 33356

American (AMR) AF: 0.0000224 AC: 1 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39572

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86116

European-Finnish (FIN) AF: 0.0000751 AC: 4 AN: 53256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000182 AC: 201 AN: 1106670

Other (OTH) AF: 0.000116 AC: 7 AN: 60166

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000263 AC: 4 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41494

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2104

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 11, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.358A>C (p.M120L) alteration is located in exon 1 (coding exon 1) of the NTF3 gene. This alteration results from a A to C substitution at nucleotide position 358, causing the methionine (M) at amino acid position 120 to be replaced by a leucine (L). 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	Benign	0.094
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.90
DEOGEN2	Benign	0.41	.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.7	.;M
PhyloP100		1.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.17
Sift	Uncertain	0.014	D;D
Sift4G	Benign	0.90	T;T
Polyphen		0.0	.;B
Vest4		0.17
MutPred		0.28		.;Gain of helix (P = 0.0496);
MVP		0.28
MPC		0.79
ClinPred		0.18	T
GERP RS		3.0
PromoterAI		0.038	Neutral
Varity_R		0.36
gMVP		0.31
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs1022358940; hg19: chr12-5603738; COSMIC: COSV105891298; COSMIC: COSV105891298;