rs886040858

Variant names:

• chr11-118581394-CAG-C
• rs886040858
• NM_001655.5:c.157_158delAG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001655.5(ARCN1):​c.157_158delAG​(p.Ser53CysfsTer39) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARCN1 NM_001655.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.50
• Publications: 0 publications found

Genes affected

ARCN1 (HGNC:649): (archain 1) This gene maps in a region, which include the mixed lineage leukemia and Friend leukemia virus integration 1 genes, where multiple disease-associated chromosome translocations occur. It is an intracellular protein. Archain sequences are well conserved among eukaryotes and this protein may play a fundamental role in eukaryotic cell biology. It has similarities to heat shock proteins and clathrin-associated proteins, and may be involved in vesicle structure or trafficking. [provided by RefSeq, Jul 2008]

ARCN1 Gene-Disease associations (from GenCC):

• short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-118581394-CAG-C is Pathogenic according to our data. Variant chr11-118581394-CAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 267208.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001655.5. 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
	ARCN1	NM_001655.5	MANE Select	c.157_158delAG	p.Ser53CysfsTer39	frameshift	Exon 2 of 10	NP_001646.2
	ARCN1	NM_001425073.1		c.157_158delAG	p.Ser53CysfsTer39	frameshift	Exon 2 of 11	NP_001412002.1
	ARCN1	NM_001425074.1		c.157_158delAG	p.Ser53CysfsTer38	frameshift	Exon 2 of 10	NP_001412003.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARCN1	ENST00000264028.5	TSL:1 MANE Select	c.157_158delAG	p.Ser53CysfsTer39	frameshift	Exon 2 of 10	ENSP00000264028.4
	ARCN1	ENST00000359415.8	TSL:1	c.280_281delAG	p.Ser94CysfsTer39	frameshift	Exon 3 of 11	ENSP00000352385.4
	ARCN1	ENST00000534182.2	TSL:5	c.157_158delAG	p.Ser53TyrfsTer43	frameshift splice_region	Exon 2 of 3	ENSP00000431676.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs886040858; hg19: chr11-118452109;