chr7-157005528-G-GCGCGGGCTGGTGGCTGGGC

Position:

• chr7-157005528-G-GCGCGGGCTGGTGGCTGGGC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_005515.4(MNX1):​c.1179_1197dupGCCCAGCCACCAGCCCGCG​(p.Pro400fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MNX1 NM_005515.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.100

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00746 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-157005528-G-GCGCGGGCTGGTGGCTGGGC is Pathogenic according to our data. Variant chr7-157005528-G-GCGCGGGCTGGTGGCTGGGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2636432.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MNX1	NM_005515.4	c.1179_1197dupGCCCAGCCACCAGCCCGCG	p.Pro400fs	frameshift_variant	3/3	ENST00000252971.11	NP_005506.3
MNX1	NM_001165255.2	c.543_561dupGCCCAGCCACCAGCCCGCG	p.Pro188fs	frameshift_variant	3/3		NP_001158727.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MNX1	ENST00000252971.11	c.1179_1197dupGCCCAGCCACCAGCCCGCG	p.Pro400fs	frameshift_variant	3/3	1	NM_005515.4	ENSP00000252971.5
MNX1	ENST00000543409.5	c.543_561dupGCCCAGCCACCAGCCCGCG	p.Pro188fs	frameshift_variant	3/3	1		ENSP00000438552.1
MNX1	ENST00000469500.5	c.55+3451_55+3469dupGCCCAGCCACCAGCCCGCG		intron_variant		1		ENSP00000475129.1
MNX1	ENST00000479817.1	c.37+4113_37+4131dupGCCCAGCCACCAGCCCGCG		intron_variant		1		ENSP00000474286.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

MNX1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2022

The MNX1 c.1179_1197dup19 variant is predicted to result in a frameshift and premature protein termination (p.Pro400Alafs*73). This variant occurs in the last exon of MNX1, near the native stop codon and is predicted to result in a frameshift and protein extension. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Downstream, a similar MNX1 insertion affecting the translation termination codon was reported in a family with Currarino syndrome (c.1205insCACCAGCCCGCGCCCCAGT p.X402Serfs70, Han et al. 2020. PubMed ID: 32571425). Both the previously-reported stop-loss variant and the duplication variant reported here, are predicted to result in an insertion and 1-basepair shift in the reading-frame resulting in a nearly identical protein extension. Taken together, the c.1179_1197dup19 (p.Pro400Alafs*73) variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-156798222;