7-157009949-AGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3BS1_Supporting

The NM_005515.4(MNX1):c.384_401dupCGCCGCCGCCGCCGCCGC(p.Ala129_Ala134dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A134A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00019 ( 3 hom. )

Failed GnomAD Quality Control

Consequence

MNX1
NM_005515.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.54

Publications

4 publications found

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-AS1 (HGNC:48954): (MNX1 antisense RNA 1 (head to head))

MNX1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_005515.4

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000432 (56/129774) while in subpopulation AFR AF = 0.000798 (28/35094). AF 95% confidence interval is 0.000566. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MNX1	NM_005515.4 link	c.384_401dupCGCCGCCGCCGCCGCCGC	p.Ala129_Ala134dup	disruptive_inframe_insertion	Exon 1 of 3	ENST00000252971.11	NP_005506.3	P50219-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MNX1	ENST00000252971.11 link	c.384_401dupCGCCGCCGCCGCCGCCGC	p.Ala129_Ala134dup	disruptive_inframe_insertion	Exon 1 of 3	1	NM_005515.4	ENSP00000252971.5	P50219-1
MNX1-AS1	ENST00000818900.1 link	n.296+1916_296+1933dupGGCGGCGGCGGCGGCGGC		intron_variant	Intron 1 of 1
MNX1-AS1	ENST00000818901.1 link	n.50+831_50+848dupGGCGGCGGCGGCGGCGGC		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.000432

AC:

AN:

129766

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000799

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000297

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000240

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000380

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000188

AC:

146

AN:

778478

Hom.:

Cov.:

AF XY:

0.000181

AC XY:

AN XY:

363718

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000607

AC:

AN:

14816

American (AMR)

AF:

0.00

AC:

AN:

1346

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4992

East Asian (EAS)

AF:

0.00

AC:

AN:

4306

South Asian (SAS)

AF:

0.000185

AC:

AN:

16176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1340

Middle Eastern (MID)

AF:

0.000631

AC:

AN:

1586

European-Non Finnish (NFE)

AF:

0.000179

AC:

127

AN:

707964

Other (OTH)

AF:

0.000231

AC:

AN:

25952

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.394

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000432

AC:

AN:

129774

Hom.:

Cov.:

AF XY:

0.000477

AC XY:

AN XY:

62922

show subpopulations

African (AFR)

AF:

0.000798

AC:

AN:

35094

American (AMR)

AF:

0.000296

AC:

AN:

13498

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3214

East Asian (EAS)

AF:

0.000241

AC:

AN:

4146

South Asian (SAS)

AF:

0.00

AC:

AN:

3814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6688

Middle Eastern (MID)

AF:

0.00

AC:

AN:

230

European-Non Finnish (NFE)

AF:

0.000380

AC:

AN:

60514

Other (OTH)

AF:

0.00

AC:

AN:

1806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00

Hom.:

1464

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.384_401dup, results in the insertion of 6 amino acid(s) of the MNX1 protein (p.Ala129_Ala134dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.5

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over