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

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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	Q5JTC6-1

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		Q5JTC6-1

Frequencies

GnomAD3 genomes

AF:

0.000428

AC:

AN:

112106

Hom.:

Cov.:

AF XY:

0.000292

AC XY:

AN XY:

34294

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

GnomAD3 exomes

AF:

0.000720

AC:

131

AN:

181875

Hom.:

AF XY:

0.000541

AC XY:

AN XY:

66495

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 SAS 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

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00691

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00109

Gnomad4 NFE exome

AF:

0.000604

Gnomad4 OTH exome

AF:

0.000890

GnomAD4 genome

AF:

0.000428

AC:

AN:

112106

Hom.:

Cov.:

AF XY:

0.000292

AC XY:

AN XY:

34294

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.0000932

Gnomad4 ASJ

AF:

0.00454

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000645

Gnomad4 NFE

AF:

0.000527

Gnomad4 OTH

AF:

0.000663

Alfa

AF:

0.00100

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

DANN

Benign

0.32

DEOGEN2

Benign

0.13

T;T

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.52

.;T

M_CAP

Benign

0.0095

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.34

N;N

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

Polyphen

0.0

B;B

Vest4

0.011

MVP

0.082

MPC

0.024

ClinPred

0.0030

GERP RS

-0.014

Varity_R

0.028

gMVP

0.23

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over