Variant 7-157005594-C-T 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_005515.4(MNX1):c.1132G>A(p.Ala378Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,448,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A378A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

MNX1
NM_005515.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.272

Variant links:

Genes affected

MNX1 (HGNC:4979): (motor neuron and pancreas homeobox 1) This gene encodes a nuclear protein, which contains a homeobox domain and is a transcription factor. Mutations in this gene result in Currarino syndrome, an autosomic dominant congenital malformation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

MNX1 links:

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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=0.13201559).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MNX1	NM_005515.4 linkuse as main transcript	c.1132G>A	p.Ala378Thr	missense_variant	3/3	ENST00000252971.11
MNX1	NM_001165255.2 linkuse as main transcript	c.496G>A	p.Ala166Thr	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MNX1	ENST00000252971.11 linkuse as main transcript	c.1132G>A	p.Ala378Thr	missense_variant	3/3	1	NM_005515.4	P2	P50219-1
MNX1	ENST00000543409.5 linkuse as main transcript	c.496G>A	p.Ala166Thr	missense_variant	3/3	1		A2	P50219-2
MNX1	ENST00000469500.5 linkuse as main transcript	c.55+3404G>A		intron_variant		1
MNX1	ENST00000479817.1 linkuse as main transcript	c.38+4066G>A		intron_variant		1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1448048

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719564

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000229

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:

0.00000181

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2022

The c.1132G>A (p.A378T) alteration is located in exon 3 (coding exon 3) of the MNX1 gene. This alteration results from a G to A substitution at nucleotide position 1132, causing the alanine (A) at amino acid position 378 to be replaced by a threonine (T). 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

0.073

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

.;T

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.43

T;T

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.9

.;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.60

N;N

REVEL

Benign

0.19

Sift

Benign

0.43

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.062

.;B

Vest4

0.049

MutPred

0.14

.;Gain of glycosylation at A378 (P = 0.044);

MVP

0.39

ClinPred

0.065

GERP RS

2.4

Varity_R

0.039

gMVP

0.17

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