chr7-157009949-A-AGCG

Variant names:

• chr7-157009949-A-AGCG
• rs548755417
• NM_005515.4:c.399_401dupCGC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_005515.4(MNX1):​c.399_401dupCGC​(p.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 0.0103 in 812,940 control chromosomes in the GnomAD database, including 8 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 0.0014 (2 hom., cov: 0)
  • Exomes 𝑓: 0.012 (6 hom.)
• Consequence: MNX1 NM_005515.4 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely 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-AGCG is Benign according to our data. Variant chr7-157009949-A-AGCG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00137 (178/129760) while in subpopulation EAS AF = 0.00314 (13/4146). AF 95% confidence interval is 0.00211. There are 2 homozygotes in GnomAd4. There are 80 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MNX1	NM_005515.4	MANE Select	c.399_401dupCGC	p.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.399_401dupCGC	p.Ala134dup	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000252971.5
	MNX1-AS1	ENST00000818900.1		n.296+1931_296+1933dupGGC		intron	N/A
	MNX1-AS1	ENST00000818901.1		n.50+846_50+848dupGGC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 178 AN: 129752 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.000311

Gnomad EAS AF: 0.00312

Gnomad SAS AF: 0.000524

Gnomad FIN AF: 0.000150

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.00167

GnomAD4 exome AF: 0.0120 AC: 8194 AN: 683180 Hom.: 6 Cov.: 28 AF XY: 0.0123 AC XY: 3913 AN XY: 319008

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

African (AFR) AF: 0.00896 AC: 123 AN: 13734

American (AMR) AF: 0.0104 AC: 13 AN: 1250

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 52 AN: 4314

East Asian (EAS) AF: 0.00776 AC: 32 AN: 4126

South Asian (SAS) AF: 0.00749 AC: 112 AN: 14954

European-Finnish (FIN) AF: 0.00386 AC: 5 AN: 1296

Middle Eastern (MID) AF: 0.00993 AC: 14 AN: 1410

European-Non Finnish (NFE) AF: 0.0123 AC: 7604 AN: 618884

Other (OTH) AF: 0.0103 AC: 239 AN: 23212

⚠️ 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: 0.00137 AC: 178 AN: 129760 Hom.: 2 Cov.: 0 AF XY: 0.00127 AC XY: 80 AN XY: 62916

African (AFR) AF: 0.00125 AC: 44 AN: 35090

American (AMR) AF: 0.00282 AC: 38 AN: 13498

Ashkenazi Jewish (ASJ) AF: 0.000311 AC: 1 AN: 3214

East Asian (EAS) AF: 0.00314 AC: 13 AN: 4146

South Asian (SAS) AF: 0.000525 AC: 2 AN: 3812

European-Finnish (FIN) AF: 0.000150 AC: 1 AN: 6686

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

European-Non Finnish (NFE) AF: 0.00126 AC: 76 AN: 60508

Other (OTH) AF: 0.00166 AC: 3 AN: 1806

Alfa AF: 0.000736 Hom.: 1464

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	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;