rs869312862

Positions:

• chrX-112791832-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The ENST00000371959.9(AMOT):​c.1926G>C​(p.Gln642His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: AMOT ENST00000371959.9 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.04

Genes affected

AMOT (HGNC:17810): (angiomotin) This gene belongs to the motin family of angiostatin binding proteins characterized by conserved coiled-coil domains and C-terminal PDZ binding motifs. The encoded protein is expressed predominantly in endothelial cells of capillaries as well as larger vessels of the placenta where it may mediate the inhibitory effect of angiostatin on tube formation and the migration of endothelial cells toward growth factors during the formation of new blood vessels. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-112791832-C-G is Pathogenic according to our data. Variant chrX-112791832-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224811.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-112791832-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMOT	NM_001113490.2	c.1926G>C	p.Gln642His	missense_variant, splice_region_variant	9/14	ENST00000371959.9	NP_001106962.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMOT	ENST00000371959.9	c.1926G>C	p.Gln642His	missense_variant, splice_region_variant	9/14	1	NM_001113490.2	ENSP00000361027	P3
AMOT	ENST00000371962.5	c.1230G>C	p.Gln410His	missense_variant, splice_region_variant	6/11	1		ENSP00000361030	A2
AMOT	ENST00000304758.5	c.699G>C	p.Gln233His	missense_variant, splice_region_variant	7/12	1		ENSP00000305557	A2
AMOT	ENST00000371958.1	c.1230G>C	p.Gln410His	missense_variant, splice_region_variant	6/9	5		ENSP00000361026	A2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cerebral visual impairment and intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Sep 09, 2015

This study shows that diverse genetic causes underlie CVI. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;T;D;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;.;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Uncertain	0.64	D;D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Pathogenic	2.9	M;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.9	D;D;D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0060	D;.;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		1.0	D;.;.;D;.
Vest4		0.68
MutPred		0.098		Gain of helix (P = 0.0496);.;.;Gain of helix (P = 0.0496);.;
MVP		0.84
MPC		0.29
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.79
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.66		Position offset: -35
DS_DL_spliceai		0.98		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869312862; hg19: chrX-112035060;