rs138948924

Positions:

• chrX-64192411-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152424.4(AMER1):​c.876G>C​(p.Lys292Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00242 in 1,210,497 control chromosomes in the GnomAD database, including 41 homozygotes. There are 787 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 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 0.013 (17 hom., 384 hem., cov: 25)
  • Exomes 𝑓: 0.0013 (24 hom. 403 hem.)
• Consequence: AMER1 NM_152424.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -2.06

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=0.001716882).
• BP6: Variant X-64192411-C-G is Benign according to our data. Variant chrX-64192411-C-G is described in ClinVar as [Benign]. Clinvar id is 133502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-64192411-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0128 (1451/113332) while in subpopulation AFR AF= 0.0448 (1400/31233). AF 95% confidence interval is 0.0429. There are 17 homozygotes in gnomad4. There are 384 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMER1	NM_152424.4	c.876G>C	p.Lys292Asn	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.876G>C	p.Lys292Asn	missense_variant	2/2	5	NM_152424.4	ENSP00000364003.4

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1450 AN: 113278 Hom.: 17 Cov.: 25 AF XY: 0.0108 AC XY: 384 AN XY: 35416

Gnomad AFR AF: 0.0449

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00323

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000354

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000112

Gnomad OTH AF: 0.00522

GnomAD3 exomes AF: 0.00373 AC: 676 AN: 181074 Hom.: 15 AF XY: 0.00251 AC XY: 165 AN XY: 65672

Gnomad AFR exome AF: 0.0475

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000542

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000371

Gnomad OTH exome AF: 0.00156

GnomAD4 exome AF: 0.00135 AC: 1480 AN: 1097165 Hom.: 24 Cov.: 34 AF XY: 0.00111 AC XY: 403 AN XY: 362583

Gnomad4 AFR exome AF: 0.0471

Gnomad4 AMR exome AF: 0.00173

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000202

Gnomad4 OTH exome AF: 0.00321

GnomAD4 genome AF: 0.0128 AC: 1451 AN: 113332 Hom.: 17 Cov.: 25 AF XY: 0.0108 AC XY: 384 AN XY: 35480

Gnomad4 AFR AF: 0.0448

Gnomad4 AMR AF: 0.00332

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000355

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000112

Gnomad4 OTH AF: 0.00515

Alfa AF: 0.00233 Hom.: 55

Bravo AF: 0.0152

ESP6500AA AF: 0.0480 AC: 184

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00432 AC: 524

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

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	0.15
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.99
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;T
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.61	.;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.69	N;N
REVEL	Benign	0.043
Sift	Uncertain	0.0070	D;D
Sift4G	Benign	0.23	T;T
Polyphen		0.012	B;B
Vest4		0.12
MutPred		0.43		Loss of ubiquitination at K292 (P = 4e-04);Loss of ubiquitination at K292 (P = 4e-04);
MVP		0.12
MPC		0.20
ClinPred		0.0077	T
GERP RS		-6.4
Varity_R		0.12
gMVP		0.071

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138948924; hg19: chrX-63412291; COSMIC: COSV57657472;