Genetic Variant NM_152424.4:c.3395A>G (chrX-64189892-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_152424.4(AMER1):c.3395A>G(p.Asn1132Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000652 in 1,073,104 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 20)

Exomes 𝑓: 0.0000065 ( 0 hom. 3 hem. )

Consequence

AMER1
NM_152424.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.173

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037955135).

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMER1	NM_152424.4 link	c.3395A>G	p.Asn1132Ser	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.3395A>G	p.Asn1132Ser	missense_variant	Exon 2 of 2	5	NM_152424.4	ENSP00000364003.4		Q5JTC6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000117

AC:

AN:

171527

Hom.:

AF XY:

0.00

AC XY:

AN XY:

60891

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000652

AC:

AN:

1073104

Hom.:

Cov.:

AF XY:

0.00000860

AC XY:

AN XY:

348942

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000131

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000838

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Oct 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1132 of the AMER1 protein (p.Asn1132Ser). This variant is present in population databases (rs560887174, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with AMER1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.92

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

T;T

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.60

.;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.038

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

L;L

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.38

.;N

REVEL

Benign

0.071

Sift

Benign

0.26

.;T

Sift4G

Uncertain

0.028

.;D

Polyphen

0.0030

B;B

Vest4

0.025

MutPred

0.10

Gain of phosphorylation at N1132 (P = 0.0336);Gain of phosphorylation at N1132 (P = 0.0336);

MVP

0.36

MPC

0.023

ClinPred

0.037

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.035

gMVP

0.12

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