11-94799455-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_130847.3(AMOTL1):​c.265G>T​(p.Gly89Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G89S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AMOTL1 NM_130847.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 2 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=0.38560346).

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>T	p.Gly89Cys	missense	Exon 3 of 13	NP_570899.1	Q8IY63-1
	AMOTL1	NM_001301007.2		c.115G>T	p.Gly39Cys	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>T	p.Gly89Cys	missense	Exon 3 of 13	ENSP00000387739.2	Q8IY63-1
	AMOTL1	ENST00000317829.12	TSL:1	c.115G>T	p.Gly39Cys	missense	Exon 2 of 12	ENSP00000320968.8	Q8IY63-2
	AMOTL1	ENST00000920894.1		c.265G>T	p.Gly89Cys	missense	Exon 3 of 13	ENSP00000590953.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 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: 9.03e-7 AC: 1 AN: 1107882

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.27
MutPred		0.37		Loss of disorder (P = 0.0238)
MVP		0.52
MPC		0.80
ClinPred		0.98	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.47
Mutation Taster		=51/49	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;