rs201092215

chrX-64190636-G-AchrX-64190636-G-CchrX-64190636-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_152424.4(AMER1):c.2651C>T(p.Pro884Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000711 in 1,210,356 control chromosomes in the GnomAD database, including 6 homozygotes. There are 280 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., 48 hem., cov: 23)
  • Exomes 𝑓: 0.00062 (4 hom. 232 hem.)
• Consequence: AMER1 NM_152424.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 1.90

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009183526).
• BP6: Variant X-64190636-G-A is Benign according to our data. Variant chrX-64190636-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 133492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-64190636-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMER1	NM_152424.4	c.2651C>T	p.Pro884Leu	missense_variant	2/2	ENST00000374869.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMER1	ENST00000374869.8	c.2651C>T	p.Pro884Leu	missense_variant	2/2	5	NM_152424.4	P1

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 177 AN: 112105 Hom.: 2 Cov.: 23 AF XY: 0.00140 AC XY: 48 AN XY: 34259

Gnomad AFR AF: 0.00438

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000941

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000375

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000527

Gnomad OTH AF: 0.000664

GnomAD3 exomes AF: 0.00108 AC: 195 AN: 181237 Hom.: 3 AF XY: 0.000909 AC XY: 61 AN XY: 67133

Gnomad AFR exome AF: 0.00421

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.000268

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000126

Gnomad NFE exome AF: 0.000665

Gnomad OTH exome AF: 0.00202

GnomAD4 exome AF: 0.000622 AC: 683 AN: 1098197 Hom.: 4 Cov.: 35 AF XY: 0.000638 AC XY: 232 AN XY: 363553

Gnomad4 AFR exome AF: 0.00390

Gnomad4 AMR exome AF: 0.00270

Gnomad4 ASJ exome AF: 0.000464

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.000476

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00158 AC: 177 AN: 112159 Hom.: 2 Cov.: 23 AF XY: 0.00140 AC XY: 48 AN XY: 34323

Gnomad4 AFR AF: 0.00437

Gnomad4 AMR AF: 0.000940

Gnomad4 ASJ AF: 0.000377

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000377

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000527

Gnomad4 OTH AF: 0.000655

Alfa AF: 0.000671 Hom.: 27

Bravo AF: 0.00173

ESP6500AA AF: 0.00194 AC: 7

ESP6500EA AF: 0.000760 AC: 5

ExAC AF: 0.00115 AC: 139

EpiCase AF: 0.000654

EpiControl AF: 0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.0092	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.63	N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.52	T
Polyphen		1.0	D;D
Vest4		0.57
MVP		0.69
MPC		0.046
ClinPred		0.025	T
GERP RS		4.8
Varity_R		0.36
gMVP		0.31

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: rs201092215; hg19: chrX-63410516; COSMIC: COSV104634901;