rs72649573

Positions:

chr1-62597945-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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 links:

DOCK7 (HGNC:):

DOCK7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 377251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-62597945-C-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANGPTL3	NM_014495.4 linkuse as main transcript	c.379C>T	p.Leu127Phe	missense_variant	1/7	ENST00000371129.4	NP_055310.1	Q9Y5C1
DOCK7	NM_001367561.1 linkuse as main transcript	c.1683-11321G>A		intron_variant		ENST00000635253.2	NP_001354490.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANGPTL3	ENST00000371129.4 linkuse as main transcript	c.379C>T	p.Leu127Phe	missense_variant	1/7	1	NM_014495.4	ENSP00000360170.3		Q9Y5C1
DOCK7	ENST00000635253.2 linkuse as main transcript	c.1683-11321G>A		intron_variant		5	NM_001367561.1	ENSP00000489124.1		Q96N67-1

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

GnomAD3 exomes

AF:

0.00696

AC:

1392

AN:

200076

Hom.:

AF XY:

0.00685

AC XY:

744

AN XY:

108644

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 SAS exome

AF:

0.000869

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

Gnomad4 AFR exome

AF:

0.00148

Gnomad4 AMR exome

AF:

0.000741

Gnomad4 ASJ exome

AF:

0.00120

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000729

Gnomad4 FIN exome

AF:

0.0128

Gnomad4 NFE exome

AF:

0.00887

Gnomad4 OTH exome

AF:

0.00585

GnomAD4 genome

AF:

0.00562

AC:

855

AN:

152000

Hom.:

Cov.:

AF XY:

0.00503

AC XY:

374

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00135

Gnomad4 AMR

AF:

0.000525

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00936

Gnomad4 NFE

AF:

0.00993

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00808

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

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2024	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 09, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ANGPTL3: BP4, BS2; DOCK7: BS2 -

Developmental and epileptic encephalopathy, 23

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

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

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

Varity_R

0.15

gMVP

0.46

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over