19-10092638-G-A

Position:

• chr19-10092638-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_031917.3(ANGPTL6):​c.1364C>T​(p.Ala455Val) 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. 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78

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]

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3635828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANGPTL6	NM_031917.3	c.1364C>T	p.Ala455Val	missense_variant	6/6	ENST00000253109.5	NP_114123.2
SHFL	NM_018381.4	c.*336G>A		3_prime_UTR_variant	8/8	ENST00000253110.16	NP_060851.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANGPTL6	ENST00000253109.5	c.1364C>T	p.Ala455Val	missense_variant	6/6	1	NM_031917.3	ENSP00000253109.3
SHFL	ENST00000253110.16	c.*336G>A		3_prime_UTR_variant	8/8	2	NM_018381.4	ENSP00000253110.10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jul 15, 2024

The c.1364C>T (p.A455V) alteration is located in exon 6 (coding exon 5) of the ANGPTL6 gene. This alteration results from a C to T substitution at nucleotide position 1364, causing the alanine (A) at amino acid position 455 to be replaced by a valine (V). 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	Uncertain	0.39
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T;T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	D;.;T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Uncertain	0.018	D
MutationAssessor	Benign	1.1	.;L;L
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.9	.;.;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.023	.;.;D
Sift4G	Benign	0.13	T;T;T
Polyphen		1.0	.;D;D
Vest4		0.33
MutPred		0.30		.;Loss of methylation at R452 (P = 0.1172);Loss of methylation at R452 (P = 0.1172);
MVP		0.79
ClinPred		0.82	D
GERP RS		4.4
Varity_R		0.16
gMVP		0.63

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: chr19-10203314;