1-11192312-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_021146.4(ANGPTL7):c.419G>A(p.Arg140His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,613,936 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (3 hom.)
• Consequence: ANGPTL7 NM_021146.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.84

Genes affected

ANGPTL7 (HGNC:24078): (angiopoietin like 7) Enables identical protein binding activity. Involved in negative regulation of vasculature development involved in avascular cornea development in camera-type eye and regulation of extracellular matrix organization. Located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

MTOR (HGNC:3942): (mechanistic target of rapamycin kinase) The protein encoded by this gene belongs to a family of phosphatidylinositol kinase-related kinases. These kinases mediate cellular responses to stresses such as DNA damage and nutrient deprivation. This kinase is a component of two distinct complexes, mTORC1, which controls protein synthesis, cell growth and proliferation, and mTORC2, which is a regulator of the actin cytoskeleton, and promotes cell survival and cell cycle progression. This protein acts as the target for the cell-cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex. Inhibitors of mTOR are used in organ transplants as immunosuppressants, and are being evaluated for their therapeutic potential in SARS-CoV-2 infections. Mutations in this gene are associated with Smith-Kingsmore syndrome and somatic focal cortical dysplasia type II. The ANGPTL7 gene is located in an intron of this gene. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067707).
• BP6: Variant 1-11192312-G-A is Benign according to our data. Variant chr1-11192312-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2638224.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANGPTL7	NM_021146.4	c.419G>A	p.Arg140His	missense_variant	2/5	ENST00000376819.4
MTOR	NM_004958.4	c.4253+6946C>T		intron_variant		ENST00000361445.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANGPTL7	ENST00000376819.4	c.419G>A	p.Arg140His	missense_variant	2/5	1	NM_021146.4	P1
MTOR	ENST00000361445.9	c.4253+6946C>T		intron_variant		1	NM_004958.4	P1

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 291 AN: 152150 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00213 AC: 536 AN: 251318 Hom.: 1 AF XY: 0.00205 AC XY: 279 AN XY: 135842

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.00677

Gnomad NFE exome AF: 0.00283

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00223 AC: 3261 AN: 1461668 Hom.: 3 Cov.: 30 AF XY: 0.00224 AC XY: 1626 AN XY: 727160

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.00525

Gnomad4 NFE exome AF: 0.00249

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00191 AC: 291 AN: 152268 Hom.: 1 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74446

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00509

Gnomad4 NFE AF: 0.00275

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00222 Hom.: 1

Bravo AF: 0.00157

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00215 AC: 261

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00196

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

MTOR: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.0091
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.94	D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.13
Sift	Benign	0.086	T
Sift4G	Benign	0.13	T
Polyphen		0.028	B
Vest4		0.21
MVP		0.63
MPC		0.12
ClinPred		0.011	T
GERP RS		3.3
Varity_R		0.095
gMVP		0.44

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: rs28991002; hg19: chr1-11252369; COSMIC: COSV63871137; COSMIC: COSV63871137;