rs2134840015

Variant names:

• chr7-157006501-G-A
• rs2134840015
• NM_005515.4:c.830C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-157006501-G-A
• chr7-157006501-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_005515.4(MNX1):​c.830C>T​(p.Ser277Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,458,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. S277W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MNX1 NM_005515.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.49
• 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-AS2 (HGNC:40278): (MNX1 antisense RNA 2)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005515.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748

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.830C>T	p.Ser277Leu	missense	Exon 2 of 3	NP_005506.3
	MNX1	NM_001165255.2		c.194C>T	p.Ser65Leu	missense	Exon 2 of 3	NP_001158727.1	P50219-2
	MNX1-AS2	NR_147077.1		n.118+77G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MNX1	ENST00000252971.11	TSL:1 MANE Select	c.830C>T	p.Ser277Leu	missense	Exon 2 of 3	ENSP00000252971.5	P50219-1
	MNX1	ENST00000543409.5	TSL:1	c.194C>T	p.Ser65Leu	missense	Exon 2 of 3	ENSP00000438552.1	P50219-2
	MNX1	ENST00000428439.1	TSL:1	c.194C>T	p.Ser65Leu	missense	Exon 2 of 3	ENSP00000401158.1	C9K088

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458992 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725568

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 85586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111382

Other (OTH) AF: 0.00 AC: 0 AN: 60232

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	33
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	0.50	N
PhyloP100		6.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.72
Sift	Benign	0.55	T
Sift4G	Benign	0.18	T
Polyphen		0.99	D
Vest4		0.67
MutPred		0.39		Gain of stability (P = 0.0773)
MVP		0.91
ClinPred		0.98	D
GERP RS		3.1
Varity_R		0.66
gMVP		0.90
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2134840015; hg19: chr7-156799195;