chrX-64190636-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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. 13/21 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 1.90

Publications

5 publications found

Variant links:

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]

AMER1 Gene-Disease associations (from GenCC):

osteopathia striata with cranial sclerosis
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, ClinGen, Genomics England PanelApp, Orphanet, G2P

AMER1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 133492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMER1	NM_152424.4 link	c.2651C>T	p.Pro884Leu	missense_variant	Exon 2 of 2	ENST00000374869.8	NP_689637.3	Q5JTC6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMER1	ENST00000374869.8 link	c.2651C>T	p.Pro884Leu	missense_variant	Exon 2 of 2	5	NM_152424.4	ENSP00000364003.4		Q5JTC6-1

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

177

AN:

112105

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00108

AC:

195

AN:

181237

AF XY:

0.000909

show subpopulations

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 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.:

Cov.:

AF XY:

0.000638

AC XY:

232

AN XY:

363553

show subpopulations

African (AFR)

AF:

0.00390

AC:

103

AN:

26402

American (AMR)

AF:

0.00270

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.000464

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54116

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.00556

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.000476

AC:

401

AN:

842127

Other (OTH)

AF:

0.00108

AC:

AN:

46092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

104

139

174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00158

AC:

177

AN:

112159

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

AN XY:

34323

show subpopulations

African (AFR)

AF:

0.00437

AC:

135

AN:

30899

American (AMR)

AF:

0.000940

AC:

AN:

10640

Ashkenazi Jewish (ASJ)

AF:

0.000377

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3556

South Asian (SAS)

AF:

0.000377

AC:

AN:

2656

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6173

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000527

AC:

AN:

53156

Other (OTH)

AF:

0.000655

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000969

Hom.:

Bravo

AF:

0.00173

ESP6500AA

AF:

0.00194

AC:

ESP6500EA

AF:

0.000760

AC:

ExAC

AF:

0.00115

AC:

139

EpiCase

AF:

0.000654

EpiControl

AF:

0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 13, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;T

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.75

.;T

M_CAP

Benign

0.042

MetaRNN

Benign

0.0092

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.63

N;N

PhyloP100

1.9

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.6

.;N

REVEL

Benign

0.20

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

1.0

D;D

Vest4

0.57

MVP

0.69

MPC

0.046

ClinPred

0.025

GERP RS

4.8

Varity_R

0.36

gMVP

0.31

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over