7-157009949-A-AGCGGCGGCGGCGGCG

Variant names:

• chr7-157009949-A-AGCGGCGGCGGCGGCG
• rs548755417
• NM_005515.4:c.387_401dupCGCCGCCGCCGCCGC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BS1 BS2

The NM_005515.4(MNX1):​c.387_401dupCGCCGCCGCCGCCGC​(p.Ala130_Ala134dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A134A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (4 hom., cov: 0)
  • Exomes 𝑓: 0.00036 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: MNX1 NM_005515.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005515.4
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00142 (184/129770) while in subpopulation AFR AF = 0.00439 (154/35092). AF 95% confidence interval is 0.00382. There are 4 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.387_401dupCGCCGCCGCCGCCGC	p.Ala130_Ala134dup	disruptive_inframe_insertion	Exon 1 of 3	NP_005506.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MNX1	ENST00000252971.11	TSL:1 MANE Select	c.387_401dupCGCCGCCGCCGCCGC	p.Ala130_Ala134dup	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000252971.5	P50219-1
	MNX1-AS1	ENST00000818900.1		n.296+1919_296+1933dupGGCGGCGGCGGCGGC		intron	N/A
	MNX1-AS1	ENST00000818901.1		n.50+834_50+848dupGGCGGCGGCGGCGGC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 185 AN: 129762 Hom.: 4 Cov.: 0

Gnomad AFR AF: 0.00442

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000445

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000480

Gnomad SAS AF: 0.000262

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000347

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000361 AC: 281 AN: 778472 Hom.: 2 Cov.: 28 AF XY: 0.000360 AC XY: 131 AN XY: 363720

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00371 AC: 55 AN: 14812

American (AMR) AF: 0.00 AC: 0 AN: 1346

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4992

East Asian (EAS) AF: 0.000232 AC: 1 AN: 4308

South Asian (SAS) AF: 0.000371 AC: 6 AN: 16176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1340

Middle Eastern (MID) AF: 0.00378 AC: 6 AN: 1586

European-Non Finnish (NFE) AF: 0.000283 AC: 200 AN: 707962

Other (OTH) AF: 0.000501 AC: 13 AN: 25950

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00142 AC: 184 AN: 129770 Hom.: 4 Cov.: 0 AF XY: 0.00116 AC XY: 73 AN XY: 62918

African (AFR) AF: 0.00439 AC: 154 AN: 35092

American (AMR) AF: 0.000445 AC: 6 AN: 13498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3214

East Asian (EAS) AF: 0.000482 AC: 2 AN: 4146

South Asian (SAS) AF: 0.000262 AC: 1 AN: 3812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6688

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 230

European-Non Finnish (NFE) AF: 0.000347 AC: 21 AN: 60514

Other (OTH) AF: 0.00 AC: 0 AN: 1806

Alfa AF: 0.00 Hom.: 1464

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

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

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;