7-157005591-C-T

Position:

• chr7-157005591-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005515.4(MNX1):​c.1135G>A​(p.Ala379Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A379V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MNX1 NM_005515.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.307

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18007487).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MNX1	NM_005515.4	c.1135G>A	p.Ala379Thr	missense_variant	3/3	ENST00000252971.11
MNX1	NM_001165255.2	c.499G>A	p.Ala167Thr	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MNX1	ENST00000252971.11	c.1135G>A	p.Ala379Thr	missense_variant	3/3	1	NM_005515.4	P2
MNX1	ENST00000543409.5	c.499G>A	p.Ala167Thr	missense_variant	3/3	1		A2
MNX1	ENST00000469500.5	c.55+3407G>A		intron_variant		1
MNX1	ENST00000479817.1	c.38+4069G>A		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 16, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	.;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.52	T;T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.1	.;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.97	N;N
REVEL	Benign	0.20
Sift	Benign	0.18	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.024	.;B
Vest4		0.11
MutPred		0.14		.;Gain of phosphorylation at A379 (P = 0.0055);
MVP		0.45
ClinPred		0.075	T
GERP RS		1.2
Varity_R		0.085
gMVP		0.15

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-156798285;