dbSNP rs1044250: ANGPTL4:p.Thr266Met (chr19-8371280-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_139314.3(ANGPTL4):c.797C>T(p.Thr266Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,613,680 control chromosomes in the GnomAD database, including 76,738 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.29 ( 6532 hom., cov: 32)

Exomes 𝑓: 0.31 ( 70206 hom. )

Consequence

ANGPTL4
NM_139314.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.785

Publications

81 publications found

Variant links:

Genes affected

ANGPTL4 (HGNC:16039): (angiopoietin like 4) This gene encodes a glycosylated, secreted protein containing a C-terminal fibrinogen domain. The encoded protein is induced by peroxisome proliferation activators and functions as a serum hormone that regulates glucose homeostasis, lipid metabolism, and insulin sensitivity. This protein can also act as an apoptosis survival factor for vascular endothelial cells and can prevent metastasis by inhibiting vascular growth and tumor cell invasion. The C-terminal domain may be proteolytically-cleaved from the full-length secreted protein. Decreased expression of this gene has been associated with type 2 diabetes. Alternative splicing results in multiple transcript variants. This gene was previously referred to as ANGPTL2 but has been renamed ANGPTL4. [provided by RefSeq, Sep 2013]

ANGPTL4 links:

RAB11B-AS1 (HGNC:44178): (RAB11B antisense RNA 1)

RAB11B-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.002986014).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139314.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANGPTL4	NM_139314.3	MANE Select	c.797C>T	p.Thr266Met	missense	Exon 6 of 7	NP_647475.1	Q9BY76-1
ANGPTL4	NM_001039667.3		c.683C>T	p.Thr228Met	missense	Exon 5 of 6	NP_001034756.1	Q9BY76-2
ANGPTL4	NR_104213.2		n.597-2913C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANGPTL4	ENST00000301455.7	TSL:1 MANE Select	c.797C>T	p.Thr266Met	missense	Exon 6 of 7	ENSP00000301455.1	Q9BY76-1
ANGPTL4	ENST00000593998.5	TSL:1	n.797C>T		non_coding_transcript_exon	Exon 6 of 8	ENSP00000472551.1	Q9BY76-1
ANGPTL4	ENST00000955923.1		c.797C>T	p.Thr266Met	missense	Exon 7 of 8	ENSP00000625982.1

Frequencies

GnomAD3 genomes

AF:

0.288

AC:

43773

AN:

151934

Hom.:

6530

Cov.:

show subpopulations

Gnomad AFR

AF:

0.237

Gnomad AMI

AF:

0.242

Gnomad AMR

AF:

0.314

Gnomad ASJ

AF:

0.362

Gnomad EAS

AF:

0.0678

Gnomad SAS

AF:

0.246

Gnomad FIN

AF:

0.393

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.314

Gnomad OTH

AF:

0.283

GnomAD2 exomes

AF:

0.304

AC:

76257

AN:

250634

AF XY:

0.301

show subpopulations

Gnomad AFR exome

AF:

0.238

Gnomad AMR exome

AF:

0.386

Gnomad ASJ exome

AF:

0.363

Gnomad EAS exome

AF:

0.0497

Gnomad FIN exome

AF:

0.398

Gnomad NFE exome

AF:

0.318

Gnomad OTH exome

AF:

0.303

GnomAD4 exome

AF:

0.306

AC:

446549

AN:

1461628

Hom.:

70206

Cov.:

AF XY:

0.304

AC XY:

220896

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.228

AC:

7633

AN:

33480

American (AMR)

AF:

0.370

AC:

16563

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.362

AC:

9453

AN:

26136

East Asian (EAS)

AF:

0.0993

AC:

3943

AN:

39700

South Asian (SAS)

AF:

0.264

AC:

22793

AN:

86256

European-Finnish (FIN)

AF:

0.392

AC:

20838

AN:

53180

Middle Eastern (MID)

AF:

0.220

AC:

1271

AN:

5766

European-Non Finnish (NFE)

AF:

0.311

AC:

346372

AN:

1111994

Other (OTH)

AF:

0.293

AC:

17683

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

22332

44664

66996

89328

111660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11186

22372

33558

44744

55930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.288

AC:

43796

AN:

152052

Hom.:

6532

Cov.:

AF XY:

0.288

AC XY:

21408

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.237

AC:

9836

AN:

41490

American (AMR)

AF:

0.314

AC:

4804

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.362

AC:

1255

AN:

3466

East Asian (EAS)

AF:

0.0684

AC:

354

AN:

5176

South Asian (SAS)

AF:

0.245

AC:

1180

AN:

4820

European-Finnish (FIN)

AF:

0.393

AC:

4154

AN:

10570

Middle Eastern (MID)

AF:

0.207

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.314

AC:

21341

AN:

67930

Other (OTH)

AF:

0.280

AC:

591

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1595

3191

4786

6382

7977

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

434

868

1302

1736

2170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.301

Hom.:

34572

Bravo

AF:

0.282

TwinsUK

AF:

0.319

AC:

1181

ALSPAC

AF:

0.289

AC:

1112

ESP6500AA

AF:

0.255

AC:

1123

ESP6500EA

AF:

0.310

AC:

2667

ExAC

AF:

0.303

AC:

36765

Asia WGS

AF:

0.176

AC:

614

AN:

3478

EpiCase

AF:

0.300

EpiControl

AF:

0.301

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

7.6

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.97

MutationAssessor

Pathogenic

3.5

PhyloP100

0.79

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.070

Sift

Benign

0.21

Sift4G

Benign

0.11

Polyphen

0.13

Vest4

0.078

MPC

0.22

ClinPred

0.044

GERP RS

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.72

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over