Variant 7-157006604-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_ModeratePM2PP3_StrongPP5

The NM_005515.4(MNX1):c.727C>T(p.Arg243Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MNX1
NM_005515.4 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.837

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:

MNX1-AS2 (HGNC:40278): (MNX1 antisense RNA 2)

MNX1-AS2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PS1

Transcript NM_005515.4 (MNX1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

PP5

Variant 7-157006604-G-A is Pathogenic according to our data. Variant chr7-157006604-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3347740.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-157006604-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MNX1	NM_005515.4 linkuse as main transcript	c.727C>T	p.Arg243Trp	missense_variant	2/3	ENST00000252971.11	NP_005506.3
MNX1-AS2	NR_147077.1 linkuse as main transcript	n.118+180G>A		intron_variant, non_coding_transcript_variant
MNX1	NM_001165255.2 linkuse as main transcript	c.91C>T	p.Arg31Trp	missense_variant	2/3		NP_001158727.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MNX1	ENST00000252971.11 linkuse as main transcript	c.727C>T	p.Arg243Trp	missense_variant	2/3	1	NM_005515.4	ENSP00000252971	P2	P50219-1
MNX1-AS2	ENST00000429228.1 linkuse as main transcript	n.118+180G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1450494

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720504

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000232

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

MNX1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2024

The MNX1 c.727C>T variant is predicted to result in the amino acid substitution p.Arg243Trp. This variant was reported in three individuals with Currarino syndrome (Ciotti et al. 2011. PubMed ID: 21915987; Garcia-Barceló et al. 2009. PubMed ID: 19853743). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

.;D;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

.;H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.9

D;D;D

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

.;D;.

Vest4

0.80

MutPred

0.85

.;Loss of disorder (P = 5e-04);.;

MVP

0.90

ClinPred

1.0

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.86

gMVP

0.94

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over