Variant 19-10092744-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_031917.3(ANGPTL6):c.1258T>C(p.Tyr420His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

ANGPTL6
NM_031917.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.25

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:

SHFL (HGNC:):

SHFL links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANGPTL6	NM_031917.3 linkuse as main transcript	c.1258T>C	p.Tyr420His	missense_variant	6/6	ENST00000253109.5	NP_114123.2	Q8NI99A0A024R7A9
SHFL	NM_018381.4 linkuse as main transcript	c.*442A>G		3_prime_UTR_variant	8/8	ENST00000253110.16	NP_060851.2	Q9NUL5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANGPTL6	ENST00000253109.5 linkuse as main transcript	c.1258T>C	p.Tyr420His	missense_variant	6/6	1	NM_031917.3	ENSP00000253109.3		Q8NI99
SHFL	ENST00000253110.16 linkuse as main transcript	c.*442A>G		3_prime_UTR_variant	8/8	2	NM_018381.4	ENSP00000253110.10		Q9NUL5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2024

The c.1258T>C (p.Y420H) alteration is located in exon 6 (coding exon 5) of the ANGPTL6 gene. This alteration results from a T to C substitution at nucleotide position 1258, causing the tyrosine (Y) at amino acid position 420 to be replaced by a histidine (H). 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.098

T;T;T

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;.;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.7

.;M;M

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.7

.;.;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

.;.;D

Sift4G

Uncertain

0.018

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.77

MutPred

0.87

.;Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);

MVP

0.87

ClinPred

1.0

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.93

gMVP

0.75

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over