chr3-51385380-C-T

Variant summary

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

The NM_006010.6(MANF):​c.38C>T​(p.Ala13Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,238,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict 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: 0.000017 ( 0 hom. )

Consequence

MANF
NM_006010.6 missense

Scores

1
2
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.76
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]

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=0.14726776).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MANFNM_006010.6 linkc.38C>T p.Ala13Val missense_variant Exon 1 of 4 ENST00000528157.7 NP_006001.5 P55145A8K878

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MANFENST00000528157.7 linkc.38C>T p.Ala13Val missense_variant Exon 1 of 4 1 NM_006010.6 ENSP00000432799.3 P55145
MANFENST00000446668.5 linkn.23C>T non_coding_transcript_exon_variant Exon 1 of 5 3 ENSP00000405280.1 H7C2D6
MANFENST00000470900.1 linkn.-29C>T upstream_gene_variant 2

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151550
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000485
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000166
AC:
18
AN:
1087308
Hom.:
0
Cov.:
32
AF XY:
0.0000136
AC XY:
7
AN XY:
514502
show subpopulations
Gnomad4 AFR exome
AF:
0.000480
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000108
Gnomad4 OTH exome
AF:
0.000114
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151656
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74144
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
Asia WGS
AF:
0.000290
AC:
1
AN:
3466

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 13, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.38C>T (p.A13V) alteration is located in exon 1 (coding exon 1) of the MANF gene. This alteration results from a C to T substitution at nucleotide position 38, causing the alanine (A) at amino acid position 13 to be replaced by a valine (V). 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
0.16
BayesDel_addAF
Benign
-0.026
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
22
DANN
Uncertain
1.0
Eigen
Benign
-0.12
Eigen_PC
Benign
0.033
FATHMM_MKL
Benign
0.38
N
LIST_S2
Benign
0.78
T
M_CAP
Uncertain
0.24
D
MetaRNN
Benign
0.15
T
MetaSVM
Benign
-0.92
T
PrimateAI
Pathogenic
0.89
D
REVEL
Benign
0.13
Sift4G
Benign
0.66
T
Vest4
0.39
MVP
0.27
MPC
0.072
ClinPred
0.96
D
GERP RS
4.1
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
3.3
gMVP
0.46

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.

Other links and lift over

dbSNP: rs545661735; hg19: chr3-51422811; API