1-212995122-T-A

Variant names:

• chr1-212995122-T-A
• NM_144567.5:c.1554A>T

Variant summary

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

The NM_144567.5(ANGEL2):​c.1554A>T​(p.Leu518Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ANGEL2 NM_144567.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.82

Genes affected

ANGEL2 (HGNC:30534): (angel homolog 2) Enables mRNA 3'-UTR binding activity. Involved in 3'-UTR-mediated mRNA stabilization and negative regulation of mitotic cell cycle. Located in Cajal body and cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGEL2	NM_144567.5	c.1554A>T	p.Leu518Phe	missense_variant	Exon 9 of 9	ENST00000366962.8	NP_653168.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGEL2	ENST00000366962.8	c.1554A>T	p.Leu518Phe	missense_variant	Exon 9 of 9	1	NM_144567.5	ENSP00000355929.3
ANGEL2	ENST00000360506.6	c.1047A>T	p.Leu349Phe	missense_variant	Exon 8 of 8	1		ENSP00000353696.2
ANGEL2	ENST00000535388.2	c.1047A>T	p.Leu349Phe	missense_variant	Exon 8 of 8	1		ENSP00000438141.2
ANGEL2	ENST00000473303.1	n.1742A>T		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1554A>T (p.L518F) alteration is located in exon 9 (coding exon 9) of the ANGEL2 gene. This alteration results from a A to T substitution at nucleotide position 1554, causing the leucine (L) at amino acid position 518 to be replaced by a phenylalanine (F). 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	0.87
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;.;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.040	N
LIST_S2	Uncertain	0.88	D;.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.1	D;D;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0060	D;D;.
Sift4G	Uncertain	0.010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.55
MutPred		0.48		Loss of stability (P = 0.1338);.;.;
MVP		0.72
MPC		0.85
ClinPred		0.97	D
GERP RS		-9.1
Varity_R		0.72
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.

Other links and lift over

hg19: chr1-213168464;