7-157005594-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.1132G>A(p.Ala378Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,448,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A378A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: MNX1 NM_005515.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.272

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=0.13201559).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MNX1	NM_005515.4	c.1132G>A	p.Ala378Thr	missense_variant	3/3	ENST00000252971.11
MNX1	NM_001165255.2	c.496G>A	p.Ala166Thr	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MNX1	ENST00000252971.11	c.1132G>A	p.Ala378Thr	missense_variant	3/3	1	NM_005515.4	P2
MNX1	ENST00000543409.5	c.496G>A	p.Ala166Thr	missense_variant	3/3	1		A2
MNX1	ENST00000469500.5	c.55+3404G>A		intron_variant		1
MNX1	ENST00000479817.1	c.38+4066G>A		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1448048 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719564

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000229

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2022

The c.1132G>A (p.A378T) alteration is located in exon 3 (coding exon 3) of the MNX1 gene. This alteration results from a G to A substitution at nucleotide position 1132, causing the alanine (A) at amino acid position 378 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.43	T;T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.60	N;N
REVEL	Benign	0.19
Sift	Benign	0.43	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.062	.;B
Vest4		0.049
MutPred		0.14		.;Gain of glycosylation at A378 (P = 0.044);
MVP		0.39
ClinPred		0.065	T
GERP RS		2.4
Varity_R		0.039
gMVP		0.17

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

LitVar

Other links and lift over

dbSNP: rs1259816325; hg19: chr7-156798288;