rs34677493

Positions:

• chrX-64192810-A-C
• chrX-64192810-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152424.4(AMER1):​c.477T>G​(p.Phe159Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,209,530 control chromosomes in the GnomAD database, including 4,387 homozygotes. There are 10,227 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (2151 hom., 3890 hem., cov: 23)
  • Exomes 𝑓: 0.019 (2236 hom. 6337 hem.)
• Consequence: AMER1 NM_152424.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -1.01

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.373587E-5).
• BP6: Variant X-64192810-A-C is Benign according to our data. Variant chrX-64192810-A-C is described in ClinVar as [Benign]. Clinvar id is 133504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-64192810-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMER1	NM_152424.4	c.477T>G	p.Phe159Leu	missense_variant	2/2	ENST00000374869.8	NP_689637.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMER1	ENST00000374869.8	c.477T>G	p.Phe159Leu	missense_variant	2/2	5	NM_152424.4	ENSP00000364003.4

Frequencies

GnomAD3 genomes AF: 0.128 AC: 14221 AN: 111475 Hom.: 2147 Cov.: 23 AF XY: 0.115 AC XY: 3868 AN XY: 33723

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0481

Gnomad ASJ AF: 0.00530

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.00246

Gnomad MID AF: 0.0340

Gnomad NFE AF: 0.00578

Gnomad OTH AF: 0.0997

GnomAD3 exomes AF: 0.0422 AC: 7715 AN: 182919 Hom.: 1074 AF XY: 0.0307 AC XY: 2070 AN XY: 67423

Gnomad AFR exome AF: 0.447

Gnomad AMR exome AF: 0.0208

Gnomad ASJ exome AF: 0.00643

Gnomad EAS exome AF: 0.000289

Gnomad SAS exome AF: 0.0331

Gnomad FIN exome AF: 0.00170

Gnomad NFE exome AF: 0.00591

Gnomad OTH exome AF: 0.0204

GnomAD4 exome AF: 0.0193 AC: 21165 AN: 1098005 Hom.: 2236 Cov.: 34 AF XY: 0.0174 AC XY: 6337 AN XY: 363419

Gnomad4 AFR exome AF: 0.453

Gnomad4 AMR exome AF: 0.0255

Gnomad4 ASJ exome AF: 0.00650

Gnomad4 EAS exome AF: 0.0000993

Gnomad4 SAS exome AF: 0.0339

Gnomad4 FIN exome AF: 0.00198

Gnomad4 NFE exome AF: 0.00510

Gnomad4 OTH exome AF: 0.0386

GnomAD4 genome AF: 0.128 AC: 14255 AN: 111525 Hom.: 2151 Cov.: 23 AF XY: 0.115 AC XY: 3890 AN XY: 33783

Gnomad4 AFR AF: 0.433

Gnomad4 AMR AF: 0.0482

Gnomad4 ASJ AF: 0.00530

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0264

Gnomad4 FIN AF: 0.00246

Gnomad4 NFE AF: 0.00578

Gnomad4 OTH AF: 0.0991

Alfa AF: 0.0269 Hom.: 1497

Bravo AF: 0.147

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00450 AC: 13

ESP6500AA AF: 0.439 AC: 1683

ESP6500EA AF: 0.00624 AC: 42

ExAC AF: 0.0469 AC: 5695

EpiCase AF: 0.00627

EpiControl AF: 0.00759

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2019	- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-1.0	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.25
DANN	Benign	0.50
DEOGEN2	Benign	0.12	T;T
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.17	.;T
MetaRNN	Benign	0.000084	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.74	N;N
REVEL	Benign	0.024
Sift	Benign	0.30	T;T
Sift4G	Benign	0.69	T;T
Polyphen		0.0	B;B
Vest4		0.0090
MutPred		0.12		Loss of methylation at K158 (P = 0.0281);Loss of methylation at K158 (P = 0.0281);
MPC		0.026
ClinPred		0.0089	T
GERP RS		0.95
Varity_R		0.030
gMVP		0.071

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: rs34677493; hg19: chrX-63412690; COSMIC: COSV57654201;