1-11192267-T-C

Position:

• chr1-11192267-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_021146.4(ANGPTL7):​c.377-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,610,574 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (25 hom.)
• Consequence: ANGPTL7 NM_021146.4 splice_region, intron
• Scores: Splicing: ADA: 0.00007366
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0990

Genes affected

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]

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:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-11192267-T-C is Benign according to our data. Variant chr1-11192267-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3387867.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTOR	NM_004958.4	c.4253+6991A>G		intron_variant		ENST00000361445.9	NP_004949.1
ANGPTL7	NM_021146.4	c.377-3T>C		splice_region_variant, intron_variant		ENST00000376819.4	NP_066969.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTOR	ENST00000361445.9	c.4253+6991A>G		intron_variant		1	NM_004958.4	ENSP00000354558.4
ANGPTL7	ENST00000376819.4	c.377-3T>C		splice_region_variant, intron_variant		1	NM_021146.4	ENSP00000366015.3

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 435 AN: 152200 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00352 AC: 884 AN: 250968 Hom.: 5 AF XY: 0.00358 AC XY: 485 AN XY: 135596

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00252

Gnomad FIN exome AF: 0.000836

Gnomad NFE exome AF: 0.00480

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00393 AC: 5734 AN: 1458256 Hom.: 25 Cov.: 29 AF XY: 0.00403 AC XY: 2926 AN XY: 725668

Gnomad4 AFR exome AF: 0.000599

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.0159

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00254

Gnomad4 FIN exome AF: 0.000957

Gnomad4 NFE exome AF: 0.00421

Gnomad4 OTH exome AF: 0.00375

GnomAD4 genome AF: 0.00286 AC: 435 AN: 152318 Hom.: 3 Cov.: 32 AF XY: 0.00256 AC XY: 191 AN XY: 74496

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00435

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00451 Hom.: 1

Bravo AF: 0.00298

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00589

EpiControl AF: 0.00468

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

Nov 01, 2024

ANGPTL7: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.35
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000074
dbscSNV1_RF	Benign	0.012
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: rs55844622; hg19: chr1-11252324;