3-134360349-C-T

Variant names:

• chr3-134360349-C-T
• rs766621996
• NM_016201.4:c.1640G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016201.4(AMOTL2):​c.1640G>A​(p.Arg547Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000762 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: AMOTL2 NM_016201.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.672

Genes affected

AMOTL2 (HGNC:17812): (angiomotin like 2) Angiomotin is a protein that binds angiostatin, a circulating inhibitor of the formation of new blood vessels (angiogenesis). Angiomotin mediates angiostatin inhibition of endothelial cell migration and tube formation in vitro. The protein encoded by this gene is related to angiomotin and is a member of the motin protein family. Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.106979966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMOTL2	NM_016201.4	c.1640G>A	p.Arg547Gln	missense_variant	Exon 7 of 10	ENST00000249883.10	NP_057285.3
AMOTL2	NM_001278683.1	c.1814G>A	p.Arg605Gln	missense_variant	Exon 7 of 10		NP_001265612.1
AMOTL2	NM_001363943.2	c.1640G>A	p.Arg547Gln	missense_variant	Exon 7 of 10		NP_001350872.1
AMOTL2	NM_001278685.2	c.1634G>A	p.Arg545Gln	missense_variant	Exon 7 of 10		NP_001265614.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMOTL2	ENST00000249883.10	c.1640G>A	p.Arg547Gln	missense_variant	Exon 7 of 10	1	NM_016201.4	ENSP00000249883.5

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000479 AC: 12 AN: 250634 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135498

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000773 AC: 113 AN: 1461810 Hom.: 0 Cov.: 32 AF XY: 0.0000743 AC XY: 54 AN XY: 727206

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000953

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74374

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000452 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1640G>A (p.R547Q) alteration is located in exon 7 (coding exon 6) of the AMOTL2 gene. This alteration results from a G to A substitution at nucleotide position 1640, causing the arginine (R) at amino acid position 547 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0097	.;T;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.13	N;N;N;N
REVEL	Benign	0.066
Sift	Benign	0.27	T;T;T;T
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.47	P;.;.;P
Vest4		0.16
MutPred		0.21		Loss of phosphorylation at S549 (P = 0.1003);Loss of phosphorylation at S549 (P = 0.1003);.;.;
MVP		0.29
MPC		0.16
ClinPred		0.022	T
GERP RS		5.2
Varity_R		0.034
gMVP		0.27

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: rs766621996; hg19: chr3-134079191; COSMIC: COSV99850570; COSMIC: COSV99850570;