7-157009949-AGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant names:

• chr7-157009949-A-AGCGGCGGCG
• rs548755417
• NM_005515.4:c.393_401dupCGCCGCCGC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_005515.4(MNX1):​c.393_401dupCGCCGCCGC​(p.Ala132_Ala134dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A134A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1095 hom., cov: 0)
  • Exomes 𝑓: 0.073 (2158 hom.)
  • Failed GnomAD Quality Control
• Consequence: MNX1 NM_005515.4 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.54
• Publications: 4 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-AS1 (HGNC:48954): (MNX1 antisense RNA 1 (head to head))

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005515.4
• BP6: Variant 7-157009949-A-AGCGGCGGCG is Benign according to our data. Variant chr7-157009949-A-AGCGGCGGCG is described in ClinVar as Benign. ClinVar VariationId is 1170017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MNX1	NM_005515.4	MANE Select	c.393_401dupCGCCGCCGC	p.Ala132_Ala134dup	disruptive_inframe_insertion	Exon 1 of 3	NP_005506.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MNX1	ENST00000252971.11	TSL:1 MANE Select	c.393_401dupCGCCGCCGC	p.Ala132_Ala134dup	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000252971.5
	MNX1-AS1	ENST00000818900.1		n.296+1925_296+1933dupGGCGGCGGC		intron	N/A
	MNX1-AS1	ENST00000818901.1		n.50+840_50+848dupGGCGGCGGC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.105 AC: 13620 AN: 129580 Hom.: 1092 Cov.: 0

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.0701

Gnomad AMR AF: 0.0872

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0717

Gnomad MID AF: 0.0244

Gnomad NFE AF: 0.0654

Gnomad OTH AF: 0.0729

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0734 AC: 56928 AN: 775888 Hom.: 2158 Cov.: 28 AF XY: 0.0734 AC XY: 26605 AN XY: 362474

African (AFR) AF: 0.200 AC: 2956 AN: 14752

American (AMR) AF: 0.0663 AC: 89 AN: 1342

Ashkenazi Jewish (ASJ) AF: 0.0344 AC: 171 AN: 4972

East Asian (EAS) AF: 0.125 AC: 535 AN: 4292

South Asian (SAS) AF: 0.120 AC: 1932 AN: 16092

European-Finnish (FIN) AF: 0.0164 AC: 22 AN: 1338

Middle Eastern (MID) AF: 0.0455 AC: 72 AN: 1582

European-Non Finnish (NFE) AF: 0.0695 AC: 49052 AN: 705676

Other (OTH) AF: 0.0812 AC: 2099 AN: 25842

GnomAD4 genome AF: 0.105 AC: 13623 AN: 129588 Hom.: 1095 Cov.: 0 AF XY: 0.107 AC XY: 6698 AN XY: 62824

African (AFR) AF: 0.188 AC: 6596 AN: 35016

American (AMR) AF: 0.0869 AC: 1172 AN: 13482

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 113 AN: 3214

East Asian (EAS) AF: 0.160 AC: 660 AN: 4132

South Asian (SAS) AF: 0.121 AC: 458 AN: 3800

European-Finnish (FIN) AF: 0.0717 AC: 479 AN: 6684

Middle Eastern (MID) AF: 0.0263 AC: 6 AN: 228

European-Non Finnish (NFE) AF: 0.0654 AC: 3954 AN: 60456

Other (OTH) AF: 0.0725 AC: 131 AN: 1806

Alfa AF: 0.0478 Hom.: 1464

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=69/31	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs548755417; hg19: chr7-156802643; COSMIC: COSV53318499; COSMIC: COSV53318499;