19-10093863-C-T

Position:

• chr19-10093863-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031917.3(ANGPTL6):​c.781G>A​(p.Ala261Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ANGPTL6 NM_031917.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.60

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21562198).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANGPTL6	NM_031917.3	c.781G>A	p.Ala261Thr	missense_variant	4/6	ENST00000253109.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANGPTL6	ENST00000253109.5	c.781G>A	p.Ala261Thr	missense_variant	4/6	1	NM_031917.3	P1
ANGPTL6	ENST00000592641.5	c.781G>A	p.Ala261Thr	missense_variant	4/6	1		P1
ANGPTL6	ENST00000589181.5	c.781G>A	p.Ala261Thr	missense_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2024

The c.781G>A (p.A261T) alteration is located in exon 4 (coding exon 3) of the ANGPTL6 gene. This alteration results from a G to A substitution at nucleotide position 781, causing the alanine (A) at amino acid position 261 to be replaced by a threonine (T). 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	0.079
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T;T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.81	T;.;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.40	.;N;N
MutationTaster	Benign	0.87	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	.;.;N
REVEL	Benign	0.17
Sift	Benign	0.42	.;.;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.84	.;P;P
Vest4		0.22
MutPred		0.42		Gain of phosphorylation at A261 (P = 0.0202);Gain of phosphorylation at A261 (P = 0.0202);Gain of phosphorylation at A261 (P = 0.0202);
MVP		0.64
ClinPred		0.45	T
GERP RS		0.83
Varity_R		0.12
gMVP		0.22

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.

Other links and lift over

hg19: chr19-10204539;