chr1-11193760-C-T

Position:

chr1-11193760-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP3BP4_StrongBP6_ModerateBS2

The NM_021146.4(ANGPTL7):c.658C>T(p.Arg220Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,084 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R220H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0034 ( 18 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 63 hom. )

Consequence

ANGPTL7
NM_021146.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.55

Variant links:

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]

ANGPTL7 links:

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]

MTOR links:

ANGPTL7 (HGNC:):

ANGPTL7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.014741689).

BP6

Variant 1-11193760-C-T is Benign according to our data. Variant chr1-11193760-C-T is described in ClinVar as [Benign]. Clinvar id is 3024678.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANGPTL7	NM_021146.4 linkuse as main transcript	c.658C>T	p.Arg220Cys	missense_variant	3/5	ENST00000376819.4	NP_066969.1	O43827
MTOR	NM_004958.4 linkuse as main transcript	c.4253+5498G>A		intron_variant		ENST00000361445.9	NP_004949.1	P42345

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANGPTL7	ENST00000376819.4 linkuse as main transcript	c.658C>T	p.Arg220Cys	missense_variant	3/5	1	NM_021146.4	ENSP00000366015.3		O43827
MTOR	ENST00000361445.9 linkuse as main transcript	c.4253+5498G>A		intron_variant		1	NM_004958.4	ENSP00000354558.4		P42345

Frequencies

GnomAD3 genomes

AF:

0.00341

AC:

518

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0432

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00425

AC:

1064

AN:

250360

Hom.:

AF XY:

0.00394

AC XY:

534

AN XY:

135418

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0432

Gnomad NFE exome

AF:

0.000922

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00184

AC:

2695

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

1305

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0451

Gnomad4 NFE exome

AF:

0.000177

Gnomad4 OTH exome

AF:

0.00129

GnomAD4 genome

AF:

0.00340

AC:

518

AN:

152246

Hom.:

Cov.:

AF XY:

0.00490

AC XY:

365

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0432

Gnomad4 NFE

AF:

0.000794

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000665

Hom.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00370

AC:

449

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

ANGPTL7: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.68

MutationAssessor

Uncertain

2.4

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-7.6

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.84

MVP

0.86

MPC

0.59

ClinPred

0.19

GERP RS

5.8

Varity_R

0.91

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over