7-157009949-AGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BS1_SupportingBS2

The NM_005515.4(MNX1):c.387_401dupCGCCGCCGCCGCCGC(p.Ala130_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 0.0014 ( 4 hom., cov: 0)

Exomes 𝑓: 0.00036 ( 2 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 -6 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 = 0.00142 (184/129770) while in subpopulation AFR AF = 0.00439 (154/35092). AF 95% confidence interval is 0.00382. There are 4 homozygotes in GnomAd4. There are 73 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

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MNX1	NM_005515.4 link	c.387_401dupCGCCGCCGCCGCCGC	p.Ala130_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.387_401dupCGCCGCCGCCGCCGC	p.Ala130_Ala134dup	disruptive_inframe_insertion	Exon 1 of 3	1	NM_005515.4	ENSP00000252971.5	P50219-1
MNX1-AS1	ENST00000818900.1 link	n.296+1919_296+1933dupGGCGGCGGCGGCGGC		intron_variant	Intron 1 of 1
MNX1-AS1	ENST00000818901.1 link	n.50+834_50+848dupGGCGGCGGCGGCGGC		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

185

AN:

129762

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00442

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000445

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000480

Gnomad SAS

AF:

0.000262

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000347

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000361

AC:

281

AN:

778472

Hom.:

Cov.:

AF XY:

0.000360

AC XY:

131

AN XY:

363720

show subpopulations

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

African (AFR)

AF:

0.00371

AC:

AN:

14812

American (AMR)

AF:

0.00

AC:

AN:

1346

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4992

East Asian (EAS)

AF:

0.000232

AC:

AN:

4308

South Asian (SAS)

AF:

0.000371

AC:

AN:

16176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1340

Middle Eastern (MID)

AF:

0.00378

AC:

AN:

1586

European-Non Finnish (NFE)

AF:

0.000283

AC:

200

AN:

707962

Other (OTH)

AF:

0.000501

AC:

AN:

25950

⚠️ 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: 0.381

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

100

<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:

0.00142

AC:

184

AN:

129770

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

AN XY:

62918

show subpopulations

African (AFR)

AF:

0.00439

AC:

154

AN:

35092

American (AMR)

AF:

0.000445

AC:

AN:

13498

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3214

East Asian (EAS)

AF:

0.000482

AC:

AN:

4146

South Asian (SAS)

AF:

0.000262

AC:

AN:

3812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6688

Middle Eastern (MID)

AF:

0.00

AC:

AN:

230

European-Non Finnish (NFE)

AF:

0.000347

AC:

AN:

60514

Other (OTH)

AF:

0.00

AC:

AN:

1806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

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 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.387_401dup, results in the insertion of 5 amino acid(s) of the MNX1 protein (p.Ala130_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