Genetic Variant ANGPTL6:p.Arg358Cys (chr19-10093499-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_031917.3(ANGPTL6):c.1072C>T(p.Arg358Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,614,168 control chromosomes in the GnomAD database, including 195 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.010 ( 11 hom., cov: 32)

Exomes 𝑓: 0.014 ( 184 hom. )

Consequence

ANGPTL6
NM_031917.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.95

Publications

10 publications found

Variant links:

Genes affected

ANGPTL6 (HGNC:23140): (angiopoietin like 6) Predicted to enable signaling receptor binding activity. Predicted to be involved in angiogenesis and cell differentiation. Located in extracellular exosome. Part of collagen-containing extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

ANGPTL6 links:

SHFL (HGNC:25649): (shiftless antiviral inhibitor of ribosomal frameshifting) This gene is an interferon stimulated gene (ISG) that inhibits viral replication. The encoded protein binds nucleic acids and inhibits programmed -1 ribosomal frameshifting required for translation by many RNA viruses. Viruses inhibited by the protein include Zika virus, dengue virus and the coronaviruses, SARS-CoV and SARS-CoV2. [provided by RefSeq, Aug 2021]

SHFL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01036942).

BP6

Variant 19-10093499-G-A is Benign according to our data. Variant chr19-10093499-G-A is described in ClinVar as Benign. ClinVar VariationId is 2649280.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0103 (1575/152314) while in subpopulation NFE AF = 0.017 (1157/68020). AF 95% confidence interval is 0.0162. There are 11 homozygotes in GnomAd4. There are 741 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1575 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031917.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANGPTL6	NM_031917.3	MANE Select	c.1072C>T	p.Arg358Cys	missense	Exon 5 of 6	NP_114123.2
ANGPTL6	NM_001321411.2		c.1072C>T	p.Arg358Cys	missense	Exon 5 of 6	NP_001308340.1	Q8NI99
ANGPTL6	NM_001387347.1		c.1072C>T	p.Arg358Cys	missense	Exon 6 of 7	NP_001374276.1	Q8NI99

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANGPTL6	ENST00000253109.5	TSL:1 MANE Select	c.1072C>T	p.Arg358Cys	missense	Exon 5 of 6	ENSP00000253109.3	Q8NI99
ANGPTL6	ENST00000592641.5	TSL:1	c.1072C>T	p.Arg358Cys	missense	Exon 5 of 6	ENSP00000467930.1	Q8NI99
ANGPTL6	ENST00000890998.1		c.1072C>T	p.Arg358Cys	missense	Exon 6 of 7	ENSP00000561057.1

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1576

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00857

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00621

Gnomad FIN

AF:

0.0117

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0170

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.0114

AC:

2856

AN:

251354

AF XY:

0.0117

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.00555

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0141

Gnomad NFE exome

AF:

0.0179

Gnomad OTH exome

AF:

0.0114

GnomAD4 exome

AF:

0.0144

AC:

21123

AN:

1461854

Hom.:

184

Cov.:

AF XY:

0.0143

AC XY:

10366

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00254

AC:

AN:

33480

American (AMR)

AF:

0.00537

AC:

240

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000918

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00660

AC:

569

AN:

86258

European-Finnish (FIN)

AF:

0.0151

AC:

804

AN:

53388

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0168

AC:

18654

AN:

1112008

Other (OTH)

AF:

0.0122

AC:

739

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1466

2932

4397

5863

7329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

672

1344

2016

2688

3360

<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:

0.0103

AC:

1575

AN:

152314

Hom.:

Cov.:

AF XY:

0.00995

AC XY:

741

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00269

AC:

112

AN:

41564

American (AMR)

AF:

0.00856

AC:

131

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0117

AC:

124

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0170

AC:

1157

AN:

68020

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

164

246

328

410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0139

Hom.:

Bravo

AF:

0.00969

TwinsUK

AF:

0.0156

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0143

AC:

123

ExAC

AF:

0.0124

AC:

1511

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0150

EpiControl

AF:

0.0157

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.017

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0068

LIST_S2

Benign

0.66

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.34

PhyloP100

3.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.5

REVEL

Benign

0.24

Sift

Uncertain

0.024

Sift4G

Benign

0.13

Polyphen

0.17

Vest4

0.27

ClinPred

0.014

GERP RS

2.3

Varity_R

0.18

gMVP

0.60

Mutation Taster

=70/30

polymorphism

(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