X-64191491-T-C

Position:

chrX-64191491-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_152424.4(AMER1):c.1796A>G(p.Tyr599Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000643 in 1,210,670 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 254 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y599H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., 9 hem., cov: 24)

Exomes 𝑓: 0.00067 ( 0 hom. 245 hem. )

Consequence

AMER1
NM_152424.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -0.113

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016792178).

BP6

Variant X-64191491-T-C is Benign according to our data. Variant chrX-64191491-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 133487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-64191491-T-C is described in Lovd as [Benign]. Variant chrX-64191491-T-C is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMER1	NM_152424.4 linkuse as main transcript	c.1796A>G	p.Tyr599Cys	missense_variant	2/2	ENST00000374869.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMER1	ENST00000374869.8 linkuse as main transcript	c.1796A>G	p.Tyr599Cys	missense_variant	2/2	5	NM_152424.4	P1	Q5JTC6-1

Frequencies

GnomAD3 genomes

AF:

0.000383

AC:

AN:

112401

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

AN XY:

34587

show subpopulations

Gnomad AFR

AF:

0.000194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000696

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000388

AC:

AN:

183220

Hom.:

AF XY:

0.000458

AC XY:

AN XY:

67686

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000626

Gnomad NFE exome

AF:

0.000807

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000670

AC:

736

AN:

1098221

Hom.:

Cov.:

AF XY:

0.000674

AC XY:

245

AN XY:

363595

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.000857

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.000382

AC:

AN:

112449

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

AN XY:

34645

show subpopulations

Gnomad4 AFR

AF:

0.000194

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000696

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000861

Hom.:

Bravo

AF:

0.000385

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00104

AC:

ExAC

AF:

0.000412

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	AMER1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 15, 2023	- -

not specified

Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Osteopathia striata with cranial sclerosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.73

CADD

Benign

9.1

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

T;T

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.79

.;T

M_CAP

Benign

0.0073

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

0.30

N;N

REVEL

Benign

0.028

Sift

Uncertain

0.0080

D;D

Sift4G

Benign

0.13

T;T

Polyphen

0.0020

B;B

Vest4

0.16

MVP

0.12

MPC

0.068

ClinPred

0.016

GERP RS

1.1

Varity_R

0.17

gMVP

0.19

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