chr7-157009949-A-AGCGGCGGCGGCGGCG

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BS1_Supporting 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: Likely_benign. The variant received -6 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. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR 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;