Genetic Variant NM_014495.4:c.379C>T (chr1-62597945-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014495.4(ANGPTL3):c.379C>T(p.Leu127Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00751 in 1,551,320 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0056 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0077 ( 55 hom. )

Consequence

ANGPTL3
NM_014495.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.99

Publications

17 publications found

Variant links:

Genes affected

ANGPTL3 (HGNC:491): (angiopoietin like 3) This gene encodes a member of a family of secreted proteins that function in angiogenesis. The encoded protein, which is expressed predominantly in the liver, is further processed into an N-terminal coiled-coil domain-containing chain and a C-terminal fibrinogen chain. The N-terminal chain is important for lipid metabolism, while the C-terminal chain may be involved in angiogenesis. Mutations in this gene cause familial hypobetalipoproteinemia type 2. [provided by RefSeq, Aug 2015]

ANGPTL3 links:

DOCK7 (HGNC:19190): (dedicator of cytokinesis 7) The protein encoded by this gene is a guanine nucleotide exchange factor (GEF) that plays a role in axon formation and neuronal polarization. The encoded protein displays GEF activity toward RAC1 and RAC3 Rho small GTPases but not toward CDC42. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

DOCK7 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 23
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

DOCK7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0075231194).

BP6

Variant 1-62597945-C-T is Benign according to our data. Variant chr1-62597945-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00563 (855/152000) while in subpopulation NFE AF = 0.00993 (674/67898). AF 95% confidence interval is 0.00931. There are 3 homozygotes in GnomAd4. There are 374 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014495.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANGPTL3	NM_014495.4	MANE Select	c.379C>T	p.Leu127Phe	missense	Exon 1 of 7	NP_055310.1	Q9Y5C1
DOCK7	NM_001367561.1	MANE Select	c.1683-11321G>A		intron	N/A	NP_001354490.1	Q96N67-1
DOCK7	NM_001330614.2		c.1683-11321G>A		intron	N/A	NP_001317543.1	Q96N67-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANGPTL3	ENST00000371129.4	TSL:1 MANE Select	c.379C>T	p.Leu127Phe	missense	Exon 1 of 7	ENSP00000360170.3	Q9Y5C1
DOCK7	ENST00000635253.2	TSL:5 MANE Select	c.1683-11321G>A		intron	N/A	ENSP00000489124.1	Q96N67-1
DOCK7	ENST00000454575.6	TSL:1	c.1683-11321G>A		intron	N/A	ENSP00000413583.2	Q96N67-2

Frequencies

GnomAD3 genomes

AF:

0.00563

AC:

855

AN:

151882

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000525

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00936

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00993

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00696

AC:

1392

AN:

200076

AF XY:

0.00685

show subpopulations

Gnomad AFR exome

AF:

0.00153

Gnomad AMR exome

AF:

0.000662

Gnomad ASJ exome

AF:

0.000812

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0120

Gnomad NFE exome

AF:

0.0110

Gnomad OTH exome

AF:

0.00659

GnomAD4 exome

AF:

0.00772

AC:

10799

AN:

1399320

Hom.:

Cov.:

AF XY:

0.00758

AC XY:

5250

AN XY:

692690

show subpopulations

African (AFR)

AF:

0.00148

AC:

AN:

30446

American (AMR)

AF:

0.000741

AC:

AN:

29672

Ashkenazi Jewish (ASJ)

AF:

0.00120

AC:

AN:

22496

East Asian (EAS)

AF:

0.00

AC:

AN:

39086

South Asian (SAS)

AF:

0.000729

AC:

AN:

74104

European-Finnish (FIN)

AF:

0.0128

AC:

653

AN:

51154

Middle Eastern (MID)

AF:

0.000737

AC:

AN:

5426

European-Non Finnish (NFE)

AF:

0.00887

AC:

9657

AN:

1089316

Other (OTH)

AF:

0.00585

AC:

337

AN:

57620

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

532

1064

1596

2128

2660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

332

664

996

1328

1660

<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:

0.00562

AC:

855

AN:

152000

Hom.:

Cov.:

AF XY:

0.00503

AC XY:

374

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41508

American (AMR)

AF:

0.000525

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000623

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00936

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00993

AC:

674

AN:

67898

Other (OTH)

AF:

0.00427

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

120

160

200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00777

Hom.:

Bravo

AF:

0.00461

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00874

AC:

ExAC

AF:

0.00718

AC:

871

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Developmental and epileptic encephalopathy, 23 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0075

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.4

PhyloP100

2.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.4

REVEL

Benign

0.15

Sift

Uncertain

0.024

Sift4G

Benign

0.12

Polyphen

0.91

Vest4

0.15

MVP

0.68

MPC

0.12

ClinPred

0.022

GERP RS

5.7

PromoterAI

-0.0030

Neutral

(source)

Varity_R

0.15

gMVP

0.46

Mutation Taster

=63/37

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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