rs754829375

Variant names:

• chr7-157005570-C-T
• rs754829375
• NM_005515.4:c.1156G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005515.4(MNX1):​c.1156G>A​(p.Glu386Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000021 in 1,431,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MNX1 NM_005515.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.30
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Currarino triad

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• permanent neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22983891).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005515.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MNX1	NM_005515.4	MANE Select	c.1156G>A	p.Glu386Lys	missense	Exon 3 of 3	NP_005506.3
	MNX1	NM_001165255.2		c.520G>A	p.Glu174Lys	missense	Exon 3 of 3	NP_001158727.1	P50219-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MNX1	ENST00000252971.11	TSL:1 MANE Select	c.1156G>A	p.Glu386Lys	missense	Exon 3 of 3	ENSP00000252971.5	P50219-1
	MNX1	ENST00000543409.5	TSL:1	c.520G>A	p.Glu174Lys	missense	Exon 3 of 3	ENSP00000438552.1	P50219-2
	MNX1	ENST00000469500.5	TSL:1	c.55+3428G>A		intron	N/A	ENSP00000475129.1	S4R464

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000501 AC: 1 AN: 199650 AF XY: 0.00000907

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1431410 Hom.: 0 Cov.: 31 AF XY: 0.00000282 AC XY: 2 AN XY: 710476

African (AFR) AF: 0.00 AC: 0 AN: 31336

American (AMR) AF: 0.00 AC: 0 AN: 41686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25392

East Asian (EAS) AF: 0.00 AC: 0 AN: 37218

South Asian (SAS) AF: 0.00 AC: 0 AN: 82574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4832

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1100180

Other (OTH) AF: 0.00 AC: 0 AN: 59008

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000171 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.055
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.23
Sift	Benign	0.38	T
Sift4G	Benign	0.15	T
Polyphen		0.64	P
Vest4		0.19
MutPred		0.15		Gain of ubiquitination at E386 (P = 0.0031)
MVP		0.75
ClinPred		0.57	D
GERP RS		4.4
Varity_R		0.24
gMVP		0.22
Mutation Taster		=72/28	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

Other links and lift over

dbSNP: rs754829375; hg19: chr7-156798264;