11-118581297-C-T

Variant names:

• chr11-118581297-C-T
• NM_001655.5:c.55C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001425076.1(ARCN1):​c.-15C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARCN1 NM_001425076.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.90
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.625
• PP5: Variant 11-118581297-C-T is Pathogenic according to our data. Variant chr11-118581297-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3377223.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001425076.1. 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
	ARCN1	NM_001655.5	MANE Select	c.55C>T	p.Arg19*	stop_gained	Exon 2 of 10	NP_001646.2
	ARCN1	NM_001425076.1		c.-15C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 11	NP_001412005.1
	ARCN1	NM_001425073.1		c.55C>T	p.Arg19*	stop_gained	Exon 2 of 11	NP_001412002.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARCN1	ENST00000264028.5	TSL:1 MANE Select	c.55C>T	p.Arg19*	stop_gained	Exon 2 of 10	ENSP00000264028.4	P48444-1
	ARCN1	ENST00000359415.8	TSL:1	c.178C>T	p.Arg60*	stop_gained	Exon 3 of 11	ENSP00000352385.4	B0YIW6
	ARCN1	ENST00000935081.1		c.55C>T	p.Arg19*	stop_gained	Exon 2 of 11	ENSP00000605140.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		2.9
Vest4		0.55
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=3/197	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

hg19: chr11-118452012; COSMIC: COSV50619043;