rs138948924

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_152424.4(AMER1):c.876G>C(p.Lys292Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00242 in 1,210,497 control chromosomes in the GnomAD database, including 41 homozygotes. There are 787 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 Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 17 hom., 384 hem., cov: 25)

Exomes 𝑓: 0.0013 ( 24 hom. 403 hem. )

Consequence

AMER1
NM_152424.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: -2.06

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001716882).

BP6

Variant X-64192411-C-G is Benign according to our data. Variant chrX-64192411-C-G is described in ClinVar as [Benign]. Clinvar id is 133502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0128 (1451/113332) while in subpopulation AFR AF = 0.0448 (1400/31233). AF 95% confidence interval is 0.0429. There are 17 homozygotes in GnomAd4. There are 384 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMER1	NM_152424.4 link	c.876G>C	p.Lys292Asn	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.876G>C	p.Lys292Asn	missense_variant	Exon 2 of 2	5	NM_152424.4	ENSP00000364003.4		Q5JTC6-1

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1450

AN:

113278

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0449

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00323

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000354

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000112

Gnomad OTH

AF:

0.00522

GnomAD2 exomes

AF:

0.00373

AC:

676

AN:

181074

AF XY:

0.00251

show subpopulations

Gnomad AFR exome

AF:

0.0475

Gnomad AMR exome

AF:

0.00161

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000371

Gnomad OTH exome

AF:

0.00156

GnomAD4 exome

AF:

0.00135

AC:

1480

AN:

1097165

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

403

AN XY:

362583

show subpopulations

African (AFR)

AF:

0.0471

AC:

1244

AN:

26395

American (AMR)

AF:

0.00173

AC:

AN:

35170

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19273

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.0000186

AC:

AN:

53851

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40439

Middle Eastern (MID)

AF:

0.00218

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.0000202

AC:

AN:

841655

Other (OTH)

AF:

0.00321

AC:

148

AN:

46046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

161

241

322

402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0128

AC:

1451

AN:

113332

Hom.:

Cov.:

AF XY:

0.0108

AC XY:

384

AN XY:

35480

show subpopulations

African (AFR)

AF:

0.0448

AC:

1400

AN:

31233

American (AMR)

AF:

0.00332

AC:

AN:

10838

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2659

East Asian (EAS)

AF:

0.00

AC:

AN:

3564

South Asian (SAS)

AF:

0.000355

AC:

AN:

2815

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6359

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000112

AC:

AN:

53408

Other (OTH)

AF:

0.00515

AC:

AN:

1554

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

106

158

211

264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00233

Hom.:

Bravo

AF:

0.0152

ESP6500AA

AF:

0.0480

AC:

184

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00432

AC:

524

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 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

0.15

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-0.99

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

T;T

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.61

.;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;M

PhyloP100

-2.1

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.69

N;N

REVEL

Benign

0.043

Sift

Uncertain

0.0070

D;D

Sift4G

Benign

0.23

T;T

Polyphen

0.012

B;B

Vest4

0.12

MutPred

0.43

Loss of ubiquitination at K292 (P = 4e-04);Loss of ubiquitination at K292 (P = 4e-04);

MVP

0.12

MPC

0.20

ClinPred

0.0077

GERP RS

-6.4

Varity_R

0.12

gMVP

0.071

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs138948924

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