X-64189947-C-A

Variant names:

• chrX-64189947-C-A
• rs777322830
• NM_152424.4:c.3340G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_152424.4(AMER1):​c.3340G>T​(p.Ala1114Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,203,921 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000012 (0 hom. 4 hem.)
• Consequence: AMER1 NM_152424.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.442
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041397423).
• BP6: Variant X-64189947-C-A is Benign according to our data. Variant chrX-64189947-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3608307.
• BS2: High Hemizygotes in GnomAdExome4 at 4 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.3340G>T	p.Ala1114Ser	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.3340G>T	p.Ala1114Ser	missense	Exon 2 of 2	ENSP00000364003.4	Q5JTC6-1

Frequencies

GnomAD3 genomes AF: 0.0000181 AC: 2 AN: 110672 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000379

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000180 AC: 3 AN: 166278 AF XY: 0.00

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: 0.0000410

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000119 AC: 13 AN: 1093249 Hom.: 0 Cov.: 35 AF XY: 0.0000111 AC XY: 4 AN XY: 359207

African (AFR) AF: 0.00 AC: 0 AN: 26366

American (AMR) AF: 0.00 AC: 0 AN: 34745

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19281

East Asian (EAS) AF: 0.00 AC: 0 AN: 30086

South Asian (SAS) AF: 0.00 AC: 0 AN: 52999

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40001

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4078

European-Non Finnish (NFE) AF: 0.0000143 AC: 12 AN: 839797

Other (OTH) AF: 0.0000218 AC: 1 AN: 45896

GnomAD4 genome AF: 0.0000181 AC: 2 AN: 110672 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 32892

African (AFR) AF: 0.00 AC: 0 AN: 30339

American (AMR) AF: 0.00 AC: 0 AN: 10457

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3485

South Asian (SAS) AF: 0.00 AC: 0 AN: 2603

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000379 AC: 2 AN: 52752

Other (OTH) AF: 0.00 AC: 0 AN: 1480

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000830 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.6
DANN	Benign	0.64
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L
PhyloP100		0.44
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.033
Sift	Benign	0.45	T
Sift4G	Benign	0.14	T
Polyphen		0.012	B
Vest4		0.034
MVP		0.16
MPC		0.024
ClinPred		0.017	T
GERP RS		1.2
Varity_R		0.047
gMVP		0.15
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs777322830; hg19: chrX-63409827;