NM_031917.3:c.371C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_031917.3(ANGPTL6):c.371C>T(p.Pro124Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000323 in 1,240,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

ANGPTL6
NM_031917.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.127

Publications

1 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 Gene-Disease associations (from GenCC):

intracranial berry aneurysm
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ANGPTL6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09550047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPTL6	NM_031917.3 link	c.371C>T	p.Pro124Leu	missense_variant	Exon 2 of 6	ENST00000253109.5	NP_114123.2	Q8NI99A0A024R7A9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ANGPTL6	ENST00000253109.5 link	c.371C>T	p.Pro124Leu	missense_variant	Exon 2 of 6	1	NM_031917.3	ENSP00000253109.3	Q8NI99
ANGPTL6	ENST00000592641.5 link	c.371C>T	p.Pro124Leu	missense_variant	Exon 2 of 6	1		ENSP00000467930.1	Q8NI99
ANGPTL6	ENST00000589181.5 link	c.371C>T	p.Pro124Leu	missense_variant	Exon 1 of 5	5		ENSP00000465597.1	K7EKF6
ANGPTL6	ENST00000586910.1 link	n.-62C>T		upstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150506

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000184

AC:

AN:

1089760

Hom.:

Cov.:

AF XY:

0.00000193

AC XY:

AN XY:

517848

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22542

American (AMR)

AF:

0.00

AC:

AN:

8096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14048

East Asian (EAS)

AF:

0.00

AC:

AN:

25794

South Asian (SAS)

AF:

0.00

AC:

AN:

25644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22130

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2914

European-Non Finnish (NFE)

AF:

0.00000216

AC:

AN:

925002

Other (OTH)

AF:

0.00

AC:

AN:

43590

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150506

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73500

show subpopulations

African (AFR)

AF:

0.0000486

AC:

AN:

41182

American (AMR)

AF:

0.00

AC:

AN:

15126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9958

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67498

Other (OTH)

AF:

0.00

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.371C>T (p.P124L) alteration is located in exon 2 (coding exon 1) of the ANGPTL6 gene. This alteration results from a C to T substitution at nucleotide position 371, causing the proline (P) at amino acid position 124 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

4.3

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0062

T;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.39

T;.;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.096

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

.;N;N

PhyloP100

-0.13

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.46

.;.;N

REVEL

Benign

0.10

Sift

Benign

0.15

.;.;T

Sift4G

Uncertain

0.035

D;D;D

Polyphen

0.0010

.;B;B

Vest4

0.086

MutPred

0.17

Gain of catalytic residue at P124 (P = 0.0374);Gain of catalytic residue at P124 (P = 0.0374);Gain of catalytic residue at P124 (P = 0.0374);

MVP

0.34

ClinPred

0.11

GERP RS

2.0

PromoterAI

-0.014

Neutral

(source)

Varity_R

0.026

gMVP

0.17

Mutation Taster

=87/13

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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NM_031917.3:c.371C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over