Variant 3-51386266-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006010.6(MANF):c.153C>G(p.Phe51Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

MANF
NM_006010.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.149

Variant links:

Genes affected

MANF (HGNC:15461): (mesencephalic astrocyte derived neurotrophic factor) The protein encoded by this gene is localized in the endoplasmic reticulum (ER) and golgi, and is also secreted. Reducing expression of this gene increases susceptibility to ER stress-induced death and results in cell proliferation. Activity of this protein is important in promoting the survival of dopaminergic neurons. The presence of polymorphisms in the N-terminal arginine-rich region, including a specific mutation that changes an ATG start codon to AGG, have been reported in a variety of solid tumors; however, these polymorphisms were later shown to exist in normal tissues and are thus no longer thought to be tumor-related. [provided by RefSeq, Apr 2014]

MANF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21403503).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MANF	NM_006010.6 link	c.153C>G	p.Phe51Leu	missense_variant	2/4	ENST00000528157.7	NP_006001.5	P55145A8K878

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MANF	ENST00000528157.7 link	c.153C>G	p.Phe51Leu	missense_variant	2/4	1	NM_006010.6	ENSP00000432799.3	P55145
MANF	ENST00000446668.5 link	n.138C>G		non_coding_transcript_exon_variant	2/5	3		ENSP00000405280.1	H7C2D6
MANF	ENST00000470900.1 link	n.858C>G		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000100

AC:

AN:

248810

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135080

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000818

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000541

AC:

AN:

1461500

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000904

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000141

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2023

The c.153C>G (p.F51L) alteration is located in exon 2 (coding exon 2) of the MANF gene. This alteration results from a C to G substitution at nucleotide position 153, causing the phenylalanine (F) at amino acid position 51 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

Pathogenic

0.89

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.78

M_CAP

Benign

0.011

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.53

PrimateAI

Uncertain

0.71

REVEL

Uncertain

0.36

Sift4G

Benign

0.55

Vest4

0.63

MVP

0.20

MPC

0.41

ClinPred

0.42

GERP RS

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.52

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over