3-134360177-C-G

Variant names:

• chr3-134360177-C-G
• rs151045996
• NM_016201.4:c.1812G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016201.4(AMOTL2):​c.1812G>C​(p.Gln604His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: AMOTL2 NM_016201.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0740

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062159926).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMOTL2	NM_016201.4	c.1812G>C	p.Gln604His	missense_variant	Exon 7 of 10	ENST00000249883.10	NP_057285.3
AMOTL2	NM_001278683.1	c.1986G>C	p.Gln662His	missense_variant	Exon 7 of 10		NP_001265612.1
AMOTL2	NM_001363943.2	c.1812G>C	p.Gln604His	missense_variant	Exon 7 of 10		NP_001350872.1
AMOTL2	NM_001278685.2	c.1806G>C	p.Gln602His	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.1812G>C	p.Gln604His	missense_variant	Exon 7 of 10	1	NM_016201.4	ENSP00000249883.5

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000248 AC: 62 AN: 249588 Hom.: 0 AF XY: 0.000281 AC XY: 38 AN XY: 135062

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.000490

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000462 AC: 676 AN: 1461720 Hom.: 0 Cov.: 32 AF XY: 0.000436 AC XY: 317 AN XY: 727148

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000576

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74346

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000320 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000164

EpiControl AF: 0.000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1812G>C (p.Q604H) alteration is located in exon 7 (coding exon 6) of the AMOTL2 gene. This alteration results from a G to C substitution at nucleotide position 1812, causing the glutamine (Q) at amino acid position 604 to be replaced by a histidine (H). 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	0.16
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0066	.;T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.044
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.062	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.49	N;N;N;N
REVEL	Benign	0.061
Sift	Benign	0.053	T;T;D;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.052	B;.;.;B
Vest4		0.17
MutPred		0.16		Gain of glycosylation at P603 (P = 0.0887);Gain of glycosylation at P603 (P = 0.0887);.;.;
MVP		0.32
MPC		0.57
ClinPred		0.047	T
GERP RS		4.1
Varity_R		0.15
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs151045996; hg19: chr3-134079019;