7-157005555-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_005515.4(MNX1):c.1171C>A(p.Pro391Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000701 in 1,553,942 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P391S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

MNX1
NM_005515.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.76

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11499733).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000735 (103/1401882) while in subpopulation NFE AF = 0.0000929 (101/1087186). AF 95% confidence interval is 0.0000777. There are 0 homozygotes in GnomAdExome4. There are 52 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MNX1	NM_005515.4 link	c.1171C>A	p.Pro391Thr	missense_variant	Exon 3 of 3	ENST00000252971.11	NP_005506.3	P50219-1
MNX1	NM_001165255.2 link	c.535C>A	p.Pro179Thr	missense_variant	Exon 3 of 3		NP_001158727.1	P50219-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MNX1	ENST00000252971.11 link	c.1171C>A	p.Pro391Thr	missense_variant	Exon 3 of 3	1	NM_005515.4	ENSP00000252971.5	P50219-1
MNX1	ENST00000543409.5 link	c.535C>A	p.Pro179Thr	missense_variant	Exon 3 of 3	1		ENSP00000438552.1	P50219-2
MNX1	ENST00000469500.5 link	c.55+3443C>A		intron_variant	Intron 1 of 1	1		ENSP00000475129.1	S4R464
MNX1	ENST00000479817.1 link	c.37+4105C>A		intron_variant	Intron 1 of 1	1		ENSP00000474286.1	S4R3G1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000246

AC:

AN:

162412

AF XY:

0.0000111

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000377

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000435

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000735

AC:

103

AN:

1401882

Hom.:

Cov.:

AF XY:

0.0000749

AC XY:

AN XY:

694280

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

29246

Gnomad4 AMR exome

AF:

0.0000531

AC:

AN:

37646

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

24678

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

34414

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

80030

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

46318

Gnomad4 NFE exome

AF:

0.0000929

AC:

101

AN:

1087186

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

57890

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.0000654

AC:

0.000065445

AN:

0.000065445

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000736

AC:

0.0000736247

AN:

0.0000736247

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000284

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000872

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 391 of the MNX1 protein (p.Pro391Thr). This variant is present in population databases (rs767605620, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MNX1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Currarino triad

Uncertain:1

Apr 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.25

.;T

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.61

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.52

T;T

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.29

MutationAssessor

Benign

1.8

.;L

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.14

Sift

Uncertain

0.015

D;D

Sift4G

Benign

0.47

T;T

Polyphen

0.063

.;B

Vest4

0.23

MVP

0.40

ClinPred

0.10

GERP RS

1.9

Varity_R

0.096

gMVP

0.39

Mutation Taster

=93/7

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

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