14-76789292-G-C

Variant names:

• chr14-76789292-G-C
• NM_015305.4:c.1949C>G

Variant summary

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

The NM_015305.4(ANGEL1):​c.1949C>G​(p.Pro650Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ANGEL1 NM_015305.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.85

Genes affected

ANGEL1 (HGNC:19961): (angel homolog 1) Enables eukaryotic initiation factor 4E binding activity and protein domain specific binding activity. Predicted to be involved in RNA phosphodiester bond hydrolysis, exonucleolytic. Located in several cellular components, including cis-Golgi network; endoplasmic reticulum; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.38908458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGEL1	NM_015305.4	c.1949C>G	p.Pro650Arg	missense_variant	Exon 10 of 10	ENST00000251089.8	NP_056120.2
ANGEL1	NM_001370747.1	c.2108C>G	p.Pro703Arg	missense_variant	Exon 12 of 12		NP_001357676.1
ANGEL1	NM_001370746.1	c.2011+1319C>G		intron_variant	Intron 11 of 11		NP_001357675.1
ANGEL1	NM_001370748.1	c.1852+1319C>G		intron_variant	Intron 9 of 9		NP_001357677.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGEL1	ENST00000251089.8	c.1949C>G	p.Pro650Arg	missense_variant	Exon 10 of 10	1	NM_015305.4	ENSP00000251089.3
ANGEL1	ENST00000557179.5	c.644C>G	p.Pro215Arg	missense_variant	Exon 5 of 5	2		ENSP00000451534.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461890 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727246

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1949C>G (p.P650R) alteration is located in exon 10 (coding exon 10) of the ANGEL1 gene. This alteration results from a C to G substitution at nucleotide position 1949, causing the proline (P) at amino acid position 650 to be replaced by an arginine (R). 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	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.1	L;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.80	N;N
REVEL	Uncertain	0.42
Sift	Benign	0.48	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.27	B;.
Vest4		0.57
MutPred		0.48		Gain of catalytic residue at S654 (P = 0);.;
MVP		0.95
MPC		0.62
ClinPred		0.49	T
GERP RS		5.7
Varity_R		0.11
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr14-77255635;