X-64191491-T-A

Variant names:

• chrX-64191491-T-A
• rs144896730
• NM_152424.4:c.1796A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152424.4(AMER1):​c.1796A>T​(p.Tyr599Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y599C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: AMER1 NM_152424.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.113
• 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: Labcorp Genetics (formerly Invitae), Illumina, ClinGen, Genomics England PanelApp, Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09357396).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMER1	NM_152424.4	MANE Select	c.1796A>T	p.Tyr599Phe	missense	Exon 2 of 2	NP_689637.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMER1	ENST00000374869.8	TSL:5 MANE Select	c.1796A>T	p.Tyr599Phe	missense	Exon 2 of 2	ENSP00000364003.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.4
DANN	Benign	0.94
DEOGEN2	Benign	0.28	T
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.11
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.038
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.51	T
Polyphen		0.31	B
Vest4		0.16
MutPred		0.25		Loss of phosphorylation at Y599 (P = 0.0387)
MVP		0.18
MPC		0.025
ClinPred		0.10	T
GERP RS		1.1
Varity_R		0.17
gMVP		0.099
Mutation Taster		=100/0	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: rs144896730; hg19: chrX-63411371;