rs137852217

Positions:

• chrX-64192215-G-A
• chrX-64192215-G-C
• chrX-64192215-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_152424.4(AMER1):​c.1072C>T​(p.Arg358*) variant causes a stop gained 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: AMER1 NM_152424.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.192

Genes affected

AMER1 (HGNC:26837): (APC membrane recruitment protein 1) The protein encoded by this gene upregulates trancriptional activation by the Wilms tumor protein and interacts with many other proteins, including CTNNB1, APC, AXIN1, and AXIN2. Defects in this gene are a cause of osteopathia striata with cranial sclerosis (OSCS). [provided by RefSeq, May 2010]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.685 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-64192215-G-A is Pathogenic according to our data. Variant chrX-64192215-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-64192215-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMER1	NM_152424.4	c.1072C>T	p.Arg358*	stop_gained	2/2	ENST00000374869.8	NP_689637.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMER1	ENST00000374869.8	c.1072C>T	p.Arg358*	stop_gained	2/2	5	NM_152424.4	ENSP00000364003.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2021	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 778 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database; This variant is associated with the following publications: (PMID: 20950377, 30694527, 19079258, 20209645, 28497491, 28179590) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 27, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 10708). This premature translational stop signal has been observed in individual(s) with osteopathia striata with cranial sclerosis (PMID: 19079258). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg358*) in the AMER1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 778 amino acid(s) of the AMER1 protein. -

Osteopathia striata with cranial sclerosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2010

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2015

- -

AMER1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 29, 2023

The AMER1 c.1072C>T variant is predicted to result in premature protein termination (p.Arg358*). This variant has been reported as a recurrent and frequently de novo finding in individuals with osteopathia striata with cranial sclerosis (Jenkins et al. 2009. PubMed ID: 19079258; Perdu et al. 2010. PubMed ID: 20209645). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in AMER1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.45	N
Vest4		0.87
GERP RS		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs137852217; hg19: chrX-63412095; COSMIC: COSV57654223;