7-157005590-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_005515.4(MNX1):c.1136C>T(p.Ala379Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,446,418 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A379T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MNX1 NM_005515.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.91

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.071891665).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000124 (18/1446418) while in subpopulation EAS AF= 0.00044 (17/38604). AF 95% confidence interval is 0.00028. There are 0 homozygotes in gnomad4_exome. There are 9 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MNX1	NM_005515.4	c.1136C>T	p.Ala379Val	missense_variant	3/3	ENST00000252971.11
MNX1	NM_001165255.2	c.500C>T	p.Ala167Val	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MNX1	ENST00000252971.11	c.1136C>T	p.Ala379Val	missense_variant	3/3	1	NM_005515.4	P2
MNX1	ENST00000543409.5	c.500C>T	p.Ala167Val	missense_variant	3/3	1		A2
MNX1	ENST00000469500.5	c.55+3408C>T		intron_variant		1
MNX1	ENST00000479817.1	c.38+4070C>T		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000272 AC: 6 AN: 220344 Hom.: 0 AF XY: 0.0000248 AC XY: 3 AN XY: 121210

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000362

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1446418 Hom.: 0 Cov.: 31 AF XY: 0.0000125 AC XY: 9 AN XY: 718664

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000440

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000338 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Currarino triad Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jan 04, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.49	T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-0.54	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.19
Sift	Benign	0.20	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.0040	.;B
Vest4		0.060
MutPred		0.15		.;Gain of sheet (P = 0.0149);
MVP		0.45
ClinPred		0.040	T
GERP RS		1.3
Varity_R		0.036
gMVP		0.18

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: rs780826565; hg19: chr7-156798284;