Genetic Variant AMER1:p.Thr625Ala (chrX-64191414-T-C) – ACMG Classification: Benign (-16 pts)

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.1873A>G(p.Thr625Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000646 in 1,210,177 control chromosomes in the GnomAD database, including 1 homozygotes. There are 241 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., 10 hem., cov: 24)

Exomes 𝑓: 0.00067 ( 1 hom. 231 hem. )

Consequence

AMER1
NM_152424.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.952

Publications

4 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=0.004825443).

BP6

Variant X-64191414-T-C is Benign according to our data. Variant chrX-64191414-T-C is described in ClinVar as Benign. ClinVar VariationId is 133489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMER1	NM_152424.4 link	c.1873A>G	p.Thr625Ala	missense_variant	Exon 2 of 2	ENST00000374869.8	NP_689637.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMER1	ENST00000374869.8 link	c.1873A>G	p.Thr625Ala	missense_variant	Exon 2 of 2	5	NM_152424.4	ENSP00000364003.4

Frequencies

GnomAD3 genomes

AF:

0.000428

AC:

AN:

112106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00147

Gnomad AMR

AF:

0.0000932

Gnomad ASJ

AF:

0.00454

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000645

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000527

Gnomad OTH

AF:

0.000663

GnomAD2 exomes

AF:

0.000720

AC:

131

AN:

181875

AF XY:

0.000541

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000732

Gnomad ASJ exome

AF:

0.00724

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000818

Gnomad NFE exome

AF:

0.000729

Gnomad OTH exome

AF:

0.000668

GnomAD4 exome

AF:

0.000668

AC:

734

AN:

1098071

Hom.:

Cov.:

AF XY:

0.000636

AC XY:

231

AN XY:

363443

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

26402

American (AMR)

AF:

0.0000568

AC:

AN:

35191

Ashkenazi Jewish (ASJ)

AF:

0.00691

AC:

134

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30203

South Asian (SAS)

AF:

0.00

AC:

AN:

54102

European-Finnish (FIN)

AF:

0.00109

AC:

AN:

40510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.000604

AC:

509

AN:

842059

Other (OTH)

AF:

0.000890

AC:

AN:

46087

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

114

152

190

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:

0.000428

AC:

AN:

112106

Hom.:

Cov.:

AF XY:

0.000292

AC XY:

AN XY:

34294

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30846

American (AMR)

AF:

0.0000932

AC:

AN:

10724

Ashkenazi Jewish (ASJ)

AF:

0.00454

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3530

South Asian (SAS)

AF:

0.00

AC:

AN:

2648

European-Finnish (FIN)

AF:

0.000645

AC:

AN:

6206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000527

AC:

AN:

53083

Other (OTH)

AF:

0.000663

AC:

AN:

1508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.000957

Hom.:

Bravo

AF:

0.000574

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00149

AC:

ExAC

AF:

0.000733

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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

0.063

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.31

(source)

DANN

Benign

0.32

DEOGEN2

Benign

0.13

T;T

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.0

.;T

M_CAP

Benign

0.0095

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.34

N;N

PhyloP100

-0.95

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.29

N;N

REVEL

Benign

0.071

Sift

Benign

0.91

T;T

Sift4G

Benign

1.0

T;T

Vest4

0.011

ClinPred

0.0030

GERP RS

-0.014

Varity_R

0.028

gMVP

0.23

Mutation Taster

=100/0

polymorphism

(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