rs137852216

Positions:

• chrX-64192230-G-A
• chrX-64192230-G-C
• chrX-64192230-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.1057C>T​(p.Arg353Ter) 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)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: AMER1 NM_152424.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 0.975

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 0.69 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-64192230-G-A is Pathogenic according to our data. Variant chrX-64192230-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-64192230-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.1057C>T	p.Arg353Ter	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.1057C>T	p.Arg353Ter	stop_gained	2/2	5	NM_152424.4	ENSP00000364003	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1098204 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 363560

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteopathia striata with cranial sclerosis Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 21, 2018	The p.Arg353X variant in AMER1 has been reported in 4 individuals with osteopath ia striata-cranial sclerosis (OSCS), occurring de novo in 2 individuals and segr egating with disease in an affected family member in 2 families (Jenkins 2009, Z icari 2012, Fradin 2017). The variant was not reported in large population datab ases, but has been reported in the COSMIC database as a somatic variant that was detected in two colorectal adenocarcinoma samples (Mutation ID: COSM6495573; ht tp://cancer.sanger.ac.uk/cosmic/). However, germline p.Arg353X variants in OSCS patients have not been associated with an increased risk of cancer (Jenkins 2009 , Zicari 2012, Fradin 2017). This nonsense variant leads to a premature terminat ion codon at position 353, and is predicted to result in a truncated protein (Je nkens 2009). Loss of function of AMER1 due to truncating germline variants is an established disease mechanism for OSCS. In summary, this variant meets criteria to be classified as pathogenic for OSCS in an X-linked dominant manner. ACMG/AM P Criteria applied: PM6_Strong; PM2; PM4; PS4_Moderate; PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.1057C>T;p.(Arg353*) variant creates a premature translational stop signal in the AMER1 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 10707; OMIM: 300647.0004; PMID: 19079258; 22716240; 27369646) - PS4. This variant is not present in population databases (rs137852216, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 19079258, 27369646) - PM6. The variant co-segregated with disease in multiple affected family members (PMID: 22716240) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2009	- -
Pathogenic, criteria provided, single submitter	provider interpretation	Women's and Children's Health, University of Otago	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 14, 2022

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 783 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32879452, 22716240, 27369646, 33504798, 19079258) -

Neoplasm Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.89
GERP RS		2.3

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: rs137852216; hg19: chrX-63412110; COSMIC: COSV57654256;