Genetic Variant AMER1:p.Arg1091Gln (chrX-64190015-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_152424.4(AMER1):c.3272G>A(p.Arg1091Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,093,802 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1091W) has been classified as Benign.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.000016 ( 0 hom. 7 hem. )

Consequence

AMER1
NM_152424.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.01

Publications

0 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: G2P, Illumina, Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

AMER1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026475787).

BS2

High Hemizygotes in GnomAdExome4 at 7 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152424.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMER1	NM_152424.4	MANE Select	c.3272G>A	p.Arg1091Gln	missense	Exon 2 of 2	NP_689637.3	Q5JTC6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMER1	ENST00000374869.8	TSL:5 MANE Select	c.3272G>A	p.Arg1091Gln	missense	Exon 2 of 2	ENSP00000364003.4	Q5JTC6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000590

AC:

AN:

169438

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000155

AC:

AN:

1093802

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

359600

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26365

American (AMR)

AF:

0.00

AC:

AN:

34835

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19242

East Asian (EAS)

AF:

0.00

AC:

AN:

30099

South Asian (SAS)

AF:

0.0000750

AC:

AN:

53303

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40228

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4113

European-Non Finnish (NFE)

AF:

0.0000155

AC:

AN:

839717

Other (OTH)

AF:

0.00

AC:

AN:

45900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000828

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Osteopathia striata with cranial sclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.0020

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.14

FATHMM_MKL

Benign

0.0098

LIST_S2

Benign

0.53

M_CAP

Benign

0.0045

MetaRNN

Benign

0.026

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.83

PhyloP100

-3.0

PrimateAI

Benign

0.19

PROVEAN

Benign

0.090

REVEL

Benign

0.030

Sift

Benign

0.51

Sift4G

Benign

0.17

Polyphen

0.0030

Vest4

0.031

MutPred

0.15

Loss of catalytic residue at R1091 (P = 0.0295)

MVP

0.17

MPC

0.026

ClinPred

0.051

GERP RS

-9.7

Varity_R

0.028

gMVP

0.076

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over