11-94799455-G-A

Variant names:

• chr11-94799455-G-A
• rs1951427058
• NM_130847.3:c.265G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_130847.3(AMOTL1):​c.265G>A​(p.Gly89Ser) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AMOTL1 NM_130847.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.87
• Publications: 0 publications found

Genes affected

AMOTL1 (HGNC:17811): (angiomotin like 1) The protein encoded by this gene is a peripheral membrane protein that is a component of tight junctions or TJs. TJs form an apical junctional structure and act to control paracellular permeability and maintain cell polarity. This protein is related to angiomotin, an angiostatin binding protein that regulates endothelial cell migration and capillary formation. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

AMOTL1 Gene-Disease associations (from GenCC):

• orofacial cleft

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.2216 (below the threshold of 3.09). Trascript score misZ: 1.2775 (below the threshold of 3.09). GenCC associations: The gene is linked to orofacial cleft.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19139269).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130847.3. 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
	AMOTL1	NM_130847.3	MANE Select	c.265G>A	p.Gly89Ser	missense	Exon 3 of 13	NP_570899.1	Q8IY63-1
	AMOTL1	NM_001301007.2		c.115G>A	p.Gly39Ser	missense	Exon 2 of 12	NP_001287936.1	Q8IY63-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMOTL1	ENST00000433060.3	TSL:1 MANE Select	c.265G>A	p.Gly89Ser	missense	Exon 3 of 13	ENSP00000387739.2	Q8IY63-1
	AMOTL1	ENST00000317829.12	TSL:1	c.115G>A	p.Gly39Ser	missense	Exon 2 of 12	ENSP00000320968.8	Q8IY63-2
	AMOTL1	ENST00000920894.1		c.265G>A	p.Gly89Ser	missense	Exon 3 of 13	ENSP00000590953.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1453686 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722206

African (AFR) AF: 0.00 AC: 0 AN: 33358

American (AMR) AF: 0.00 AC: 0 AN: 43526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25958

East Asian (EAS) AF: 0.00 AC: 0 AN: 39518

South Asian (SAS) AF: 0.00 AC: 0 AN: 84546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107882

Other (OTH) AF: 0.00 AC: 0 AN: 60128

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.057
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.026	B
Vest4		0.21
MutPred		0.26		Gain of phosphorylation at G89 (P = 0.0254)
MVP		0.35
MPC		0.77
ClinPred		0.79	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.090
gMVP		0.36
Mutation Taster		=61/39	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: rs1951427058; hg19: chr11-94532621;