11-94799669-C-T

Position:

• chr11-94799669-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_130847.3(AMOTL1):​c.479C>T​(p.Pro160Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AMOTL1 NM_130847.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 5.76

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-94799669-C-T is Pathogenic according to our data. Variant chr11-94799669-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 929484.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMOTL1	NM_130847.3	c.479C>T	p.Pro160Leu	missense_variant	3/13	ENST00000433060.3	NP_570899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMOTL1	ENST00000433060.3	c.479C>T	p.Pro160Leu	missense_variant	3/13	1	NM_130847.3	ENSP00000387739.2
AMOTL1	ENST00000317829.12	c.329C>T	p.Pro110Leu	missense_variant	2/12	1		ENSP00000320968.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 08, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 160 of the AMOTL1 protein (p.Pro160Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of AMOTL1-related conditions (PMID: 33026150, 36751037; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 929484). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2022	De novo variant with confirmed parentage in a patient with cleft lip and palate, imperforate anus, and dysmorphic features in the published literature (Rips et al., 2021); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 33026150) -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2024

The c.479C>T (p.P160L) alteration is located in exon 3 (coding exon 3) of the AMOTL1 gene. This alteration results from a C to T substitution at nucleotide position 479, causing the proline (P) at amino acid position 160 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with AMOTL1-related orofacial clefts (Rips, 2021; Strong, 2023). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Hypertelorism;C0080218:Tethered cord;C0158646:Cleft lip/palate;C0857379:Abnormal pinna morphology;C1858091:Long fingers;na:imperforate anus with fistula Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Hadassah Hebrew University Medical Center

Jun 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	.;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-8.6	D;D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.43	B;P
Vest4		0.85
MutPred		0.26		.;Loss of helix (P = 0.0558);
MVP		0.28
MPC		0.78
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.84
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs1951433087; hg19: chr11-94532835; COSMIC: COSV54416489; COSMIC: COSV54416489;