7-157005560-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_005515.4(MNX1):c.1166C>T(p.Ser389Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000307 in 1,561,544 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: MNX1 NM_005515.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.838

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038835138).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000526 (8/152060) while in subpopulation SAS AF= 0.00103 (5/4832). AF 95% confidence interval is 0.000408. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MNX1	NM_005515.4	c.1166C>T	p.Ser389Leu	missense_variant	3/3	ENST00000252971.11
MNX1	NM_001165255.2	c.530C>T	p.Ser177Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MNX1	ENST00000252971.11	c.1166C>T	p.Ser389Leu	missense_variant	3/3	1	NM_005515.4	P2
MNX1	ENST00000543409.5	c.530C>T	p.Ser177Leu	missense_variant	3/3	1		A2
MNX1	ENST00000469500.5	c.55+3438C>T		intron_variant		1
MNX1	ENST00000479817.1	c.38+4100C>T		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 151952 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000638 AC: 11 AN: 172340 Hom.: 0 AF XY: 0.0000731 AC XY: 7 AN XY: 95738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000872

Gnomad SAS exome AF: 0.000372

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.0000284 AC: 40 AN: 1409484 Hom.: 0 Cov.: 31 AF XY: 0.0000429 AC XY: 30 AN XY: 698500

Gnomad4 AFR exome AF: 0.0000339

Gnomad4 AMR exome AF: 0.0000257

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000397

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.0000688

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152060 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74330

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000776 AC: 9

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

Invitae

Oct 09, 2022

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 389 of the MNX1 protein (p.Ser389Leu). This variant is present in population databases (rs200578176, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MNX1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C15". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	19
Dann	Benign	0.96
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.78
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.49	T;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-0.42	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.14
Sift	Benign	0.058	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.013	.;B
Vest4		0.14
MVP		0.51
ClinPred		0.30	T
GERP RS		2.3
Varity_R		0.062
gMVP		0.23

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: rs200578176; hg19: chr7-156798254;