19-10093863-C-T

Variant names:

• chr19-10093863-C-T
• NM_031917.3:c.781G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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. 16/22 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
• Publications: 0 publications found

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

ACMG classification

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=0.21562198).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031917.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGPTL6	NM_031917.3	MANE Select	c.781G>A	p.Ala261Thr	missense	Exon 4 of 6	NP_114123.2
	ANGPTL6	NM_001321411.2		c.781G>A	p.Ala261Thr	missense	Exon 4 of 6	NP_001308340.1	Q8NI99
	ANGPTL6	NM_001387347.1		c.781G>A	p.Ala261Thr	missense	Exon 5 of 7	NP_001374276.1	Q8NI99

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGPTL6	ENST00000253109.5	TSL:1 MANE Select	c.781G>A	p.Ala261Thr	missense	Exon 4 of 6	ENSP00000253109.3	Q8NI99
	ANGPTL6	ENST00000592641.5	TSL:1	c.781G>A	p.Ala261Thr	missense	Exon 4 of 6	ENSP00000467930.1	Q8NI99
	ANGPTL6	ENST00000890998.1		c.781G>A	p.Ala261Thr	missense	Exon 5 of 7	ENSP00000561057.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.40	N
PhyloP100		3.6
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.17
Sift	Benign	0.42	T
Sift4G	Benign	0.40	T
Polyphen		0.84	P
Vest4		0.22
MutPred		0.42		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
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

hg19: chr19-10204539;