7-157009949-AGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCGGCGGCGGCGGCG

Variant names:

• chr7-157009949-A-AGCGGCG
• rs548755417
• NM_005515.4:c.396_401dupCGCCGC

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.396_401dupCGCCGC​(p.Ala133_Ala134dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.738 in 905,840 control chromosomes in the GnomAD database, including 239,175 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A134A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.78 (39716 hom., cov: 0)
  • Exomes 𝑓: 0.73 (199459 hom.)
• Consequence: MNX1 NM_005515.4 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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-AGCGGCG is Benign according to our data. Variant chr7-157009949-A-AGCGGCG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.833 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.396_401dupCGCCGC	p.Ala133_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.396_401dupCGCCGC	p.Ala133_Ala134dup	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000252971.5
	MNX1-AS1	ENST00000818900.1		n.296+1928_296+1933dupGGCGGC		intron	N/A
	MNX1-AS1	ENST00000818901.1		n.50+843_50+848dupGGCGGC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.775 AC: 100357 AN: 129486 Hom.: 39718 Cov.: 0

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.718

Gnomad AMR AF: 0.801

Gnomad ASJ AF: 0.850

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.830

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.839

Gnomad OTH AF: 0.829

GnomAD4 exome AF: 0.732 AC: 568053 AN: 776346 Hom.: 199459 Cov.: 28 AF XY: 0.729 AC XY: 264413 AN XY: 362704

African (AFR) AF: 0.618 AC: 9076 AN: 14688

American (AMR) AF: 0.528 AC: 707 AN: 1340

Ashkenazi Jewish (ASJ) AF: 0.731 AC: 3643 AN: 4982

East Asian (EAS) AF: 0.417 AC: 1779 AN: 4268

South Asian (SAS) AF: 0.590 AC: 9497 AN: 16104

European-Finnish (FIN) AF: 0.168 AC: 225 AN: 1338

Middle Eastern (MID) AF: 0.697 AC: 1106 AN: 1586

European-Non Finnish (NFE) AF: 0.742 AC: 523895 AN: 706174

Other (OTH) AF: 0.701 AC: 18125 AN: 25866

GnomAD4 genome AF: 0.775 AC: 100361 AN: 129494 Hom.: 39716 Cov.: 0 AF XY: 0.770 AC XY: 48391 AN XY: 62806

African (AFR) AF: 0.685 AC: 23985 AN: 34990

American (AMR) AF: 0.801 AC: 10791 AN: 13472

Ashkenazi Jewish (ASJ) AF: 0.850 AC: 2727 AN: 3210

East Asian (EAS) AF: 0.482 AC: 1989 AN: 4130

South Asian (SAS) AF: 0.629 AC: 2386 AN: 3794

European-Finnish (FIN) AF: 0.830 AC: 5540 AN: 6674

Middle Eastern (MID) AF: 0.823 AC: 186 AN: 226

European-Non Finnish (NFE) AF: 0.839 AC: 50712 AN: 60430

Other (OTH) AF: 0.830 AC: 1492 AN: 1798

Alfa AF: 0.496 Hom.: 1464

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	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: COSV53317528; COSMIC: COSV53317528;