X-64190015-C-T

Variant names:

• chrX-64190015-C-T
• rs761842441
• NM_152424.4:c.3272G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 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: 22)
  • Exomes 𝑓: 0.000016 (0 hom. 7 hem.)
• Consequence: AMER1 NM_152424.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.01

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026475787).
• BS2: High Hemizygotes in GnomAdExome4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMER1	NM_152424.4	c.3272G>A	p.Arg1091Gln	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	c.3272G>A	p.Arg1091Gln	missense_variant	Exon 2 of 2	5	NM_152424.4	ENSP00000364003.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000590 AC: 1 AN: 169438 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 57602

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: 0.0000573

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000155 AC: 17 AN: 1093802 Hom.: 0 Cov.: 35 AF XY: 0.0000195 AC XY: 7 AN XY: 359600

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: 0.0000750

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000155

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteopathia striata with cranial sclerosis Uncertain:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.3272G>A(p.Arg1091Gln) in the AMER1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.001% in the gnomAD Exomes. The amino acid Arg at position 1091 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster - Polymorphism) predict no damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0020
DANN	Benign	0.66
DEOGEN2	Benign	0.14	T;T
FATHMM_MKL	Benign	0.0098	N
LIST_S2	Benign	0.53	.;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.026	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L;L
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.090	.;N
REVEL	Benign	0.030
Sift	Benign	0.51	.;T
Sift4G	Benign	0.17	.;T
Polyphen		0.0030	B;B
Vest4		0.031
MutPred		0.15		Loss of catalytic residue at R1091 (P = 0.0295);Loss of catalytic residue at R1091 (P = 0.0295);
MVP		0.17
MPC		0.026
ClinPred		0.051	T
GERP RS		-9.7
Varity_R		0.028
gMVP		0.076

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

Other links and lift over

dbSNP: rs761842441; hg19: chrX-63409895;