rs17036508

Variant names:

• chr1-11195977-T-C
• rs17036508
• NM_021146.4:c.*954T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021146.4(ANGPTL7):​c.*954T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0909 in 152,254 control chromosomes in the GnomAD database, including 1,025 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.091 (1025 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: ANGPTL7 NM_021146.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.260
• Publications: 16 publications found

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]

MTOR Gene-Disease associations (from GenCC):

• macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPTL7	NM_021146.4	c.*954T>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000376819.4	NP_066969.1
MTOR	NM_004958.4	c.4253+3281A>G		intron_variant	Intron 28 of 57	ENST00000361445.9	NP_004949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPTL7	ENST00000376819.4	c.*954T>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_021146.4	ENSP00000366015.3
MTOR	ENST00000361445.9	c.4253+3281A>G		intron_variant	Intron 28 of 57	1	NM_004958.4	ENSP00000354558.4

Frequencies

GnomAD3 genomes AF: 0.0907 AC: 13803 AN: 152136 Hom.: 1015 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.0691

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.0535

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0238

Gnomad OTH AF: 0.0922

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0909 AC: 13846 AN: 152254 Hom.: 1025 Cov.: 32 AF XY: 0.0952 AC XY: 7090 AN XY: 74454

African (AFR) AF: 0.181 AC: 7504 AN: 41510

American (AMR) AF: 0.134 AC: 2048 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0691 AC: 240 AN: 3472

East Asian (EAS) AF: 0.131 AC: 677 AN: 5186

South Asian (SAS) AF: 0.198 AC: 954 AN: 4828

European-Finnish (FIN) AF: 0.0535 AC: 568 AN: 10612

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0238 AC: 1618 AN: 68024

Other (OTH) AF: 0.0926 AC: 196 AN: 2116

Alfa AF: 0.0446 Hom.: 373

Bravo AF: 0.0977

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.2
DANN	Benign	0.78
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17036508; hg19: chr1-11256034;