Genetic Variant MNX1:p.Pro18dup (chr7-157010297-T-TGGG) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PM4_Supporting

The NM_005515.4(MNX1):c.51_53dupCCC(p.Pro18dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,416,434 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MNX1
NM_005515.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.78

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_005515.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MNX1	NM_005515.4 link	c.51_53dupCCC	p.Pro18dup	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.51_53dupCCC	p.Pro18dup	disruptive_inframe_insertion	Exon 1 of 3	1	NM_005515.4	ENSP00000252971.5	P50219-1
MNX1-AS1	ENST00000818900.1 link	n.296+2256_296+2258dupGGG		intron_variant	Intron 1 of 1
MNX1-AS1	ENST00000818901.1 link	n.50+1171_50+1173dupGGG		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1416434

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703834

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

29816

American (AMR)

AF:

0.00

AC:

AN:

41180

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24740

East Asian (EAS)

AF:

0.00

AC:

AN:

35276

South Asian (SAS)

AF:

0.00

AC:

AN:

82004

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49962

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5296

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1090020

Other (OTH)

AF:

0.00

AC:

AN:

58140

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.8

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over