1-11193627-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_021146.4(ANGPTL7):c.525G>T(p.Gln175His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00562 in 1,612,570 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (42 hom.)
• Consequence: ANGPTL7 NM_021146.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.48

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06890127).
• BP6: Variant 1-11193627-G-T is Benign according to our data. Variant chr1-11193627-G-T is described in ClinVar as [Benign]. Clinvar id is 1701093.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANGPTL7	NM_021146.4	c.525G>T	p.Gln175His	missense_variant	3/5	ENST00000376819.4
MTOR	NM_004958.4	c.4253+5631C>A		intron_variant		ENST00000361445.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANGPTL7	ENST00000376819.4	c.525G>T	p.Gln175His	missense_variant	3/5	1	NM_021146.4	P1
MTOR	ENST00000361445.9	c.4253+5631C>A		intron_variant		1	NM_004958.4	P1

Frequencies

GnomAD3 genomes AF: 0.00329 AC: 501 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00623

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00343 AC: 857 AN: 249550 Hom.: 5 AF XY: 0.00343 AC XY: 462 AN XY: 134780

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000581

Gnomad ASJ exome AF: 0.000810

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000744

Gnomad NFE exome AF: 0.00695

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00586 AC: 8563 AN: 1460294 Hom.: 42 Cov.: 31 AF XY: 0.00570 AC XY: 4141 AN XY: 726358

Gnomad4 AFR exome AF: 0.00126

Gnomad4 AMR exome AF: 0.000628

Gnomad4 ASJ exome AF: 0.00108

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000956

Gnomad4 NFE exome AF: 0.00740

Gnomad4 OTH exome AF: 0.00315

GnomAD4 genome AF: 0.00330 AC: 502 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00269 AC XY: 200 AN XY: 74446

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00625

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00464 Hom.: 3

Bravo AF: 0.00305

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00361 AC: 438

EpiCase AF: 0.00376

EpiControl AF: 0.00540

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

MTOR: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.069	T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.33		Loss of MoRF binding (P = 0.1044);
MVP		0.88
MPC		0.50
ClinPred		0.042	T
GERP RS		5.8
Varity_R		0.92
gMVP		0.96

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: rs28991009; hg19: chr1-11253684;