14-76789292-G-T

Variant names:

• chr14-76789292-G-T
• rs1372811579
• NM_015305.4:c.1949C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015305.4(ANGEL1):​c.1949C>A​(p.Pro650His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P650R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANGEL1 NM_015305.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.85
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36140448).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015305.4. 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
	ANGEL1	NM_015305.4	MANE Select	c.1949C>A	p.Pro650His	missense	Exon 10 of 10	NP_056120.2	Q9UNK9
	ANGEL1	NM_001370747.1		c.2108C>A	p.Pro703His	missense	Exon 12 of 12	NP_001357676.1
	ANGEL1	NM_001370746.1		c.2011+1319C>A		intron	N/A	NP_001357675.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGEL1	ENST00000251089.8	TSL:1 MANE Select	c.1949C>A	p.Pro650His	missense	Exon 10 of 10	ENSP00000251089.3	Q9UNK9
	ANGEL1	ENST00000851327.1		c.2108C>A	p.Pro703His	missense	Exon 12 of 12	ENSP00000521386.1
	ANGEL1	ENST00000557497.2	TSL:2	c.1988C>A	p.Pro663His	missense	Exon 11 of 11	ENSP00000498076.2	A0A3B3IU54

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461890 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	0.84	L
PhyloP100		4.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.43	N
REVEL	Uncertain	0.38
Sift	Benign	0.17	T
Sift4G	Benign	0.31	T
Polyphen		0.14	B
Vest4		0.49
MutPred		0.49		Gain of catalytic residue at S654 (P = 0)
MVP		0.95
MPC		0.34
ClinPred		0.75	D
GERP RS		5.7
Varity_R		0.11
gMVP		0.56
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs1372811579; hg19: chr14-77255635;