19-10096062-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.502G>A(p.Ala168Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000754 in 1,325,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A168P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: ANGPTL6 NM_031917.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.696

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=0.16583052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANGPTL6	NM_031917.3	c.502G>A	p.Ala168Thr	missense_variant	2/6	ENST00000253109.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANGPTL6	ENST00000253109.5	c.502G>A	p.Ala168Thr	missense_variant	2/6	1	NM_031917.3	P1
ANGPTL6	ENST00000592641.5	c.502G>A	p.Ala168Thr	missense_variant	2/6	1		P1
ANGPTL6	ENST00000589181.5	c.502G>A	p.Ala168Thr	missense_variant	1/5	5
ANGPTL6	ENST00000586910.1	n.70G>A		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.54e-7 AC: 1 AN: 1325820 Hom.: 0 Cov.: 31 AF XY: 0.00000152 AC XY: 1 AN XY: 658038

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.55e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Apr 22, 2022

The c.502G>A (p.A168T) alteration is located in exon 2 (coding exon 1) of the ANGPTL6 gene. This alteration results from a G to A substitution at nucleotide position 502, causing the alanine (A) at amino acid position 168 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	0.091
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.023	T;T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.029
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	T;.;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.91	D;D;D
PrimateAI	Uncertain	0.67	T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.45	.;B;B
Vest4		0.074
MutPred		0.35		Loss of MoRF binding (P = 0.1058);Loss of MoRF binding (P = 0.1058);Loss of MoRF binding (P = 0.1058);
MVP		0.70
ClinPred		0.90	D
GERP RS		4.4
Varity_R		0.19
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr19-10206738;