14-20693685-A-G

Position:

• chr14-20693685-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_001097577.3(ANG):​c.121A>G​(p.Lys41Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K41I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANG NM_001097577.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.767

Genes affected

ANG (HGNC:483): (angiogenin) The protein encoded by this gene is a member of the RNase A superfamily though it has relatively weak ribonucleolytic activity. This protein is a potent mediator of new blood vessel formation and thus, in addition to the name RNase5, is commonly called angiogenin. This protein induces angiogenesis after binding to actin on the surface of endothelial cells. This protein also accumulates at the nucleolus where it stimulates ribosomal transcription. Under stress conditions this protein translocates to the cytosol where it hydrolyzes cellular tRNAs and influences protein synthesis. A signal peptide is cleaved from the precursor protein to produce a mature protein which contains a nuclear localization signal, a cell binding motif, and a catalytic domain. This protein has been shown to be both neurotrophic and neuroprotective and the mature protein has antimicrobial activity against some bacteria and fungi, including S. pneumoniae and C. albicans. Due to its effect on rRNA production and angiogenesis this gene plays important roles in cell growth and tumor progression. Mutations in this gene are associated with progression of amyotrophic lateral sclerosis (ALS). This gene and the neighboring RNase4 gene share promoters and 5' exons though each gene then splices to a distinct 3' exon containing the complete coding region of each gene. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2020]

RNASE4 (HGNC:10047): (ribonuclease A family member 4) The protein encoded by this gene belongs to the pancreatic ribonuclease family. It plays an important role in mRNA cleavage and has marked specificity towards the 3' side of uridine nucleotides. Alternative splicing results in four transcript variants encoding the same protein. This gene and the gene that encodes angiogenin share promoters and 5' exons. Each gene splices to a unique downstream exon that contains its complete coding region. [provided by RefSeq, Aug 2013]

EGILA (HGNC:54482): (EGFR interacting lncRNA)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-20693686-A-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839
• PP5: Variant 14-20693685-A-G is Pathogenic according to our data. Variant chr14-20693685-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 18075.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANG	NM_001097577.3	c.121A>G	p.Lys41Glu	missense_variant	2/2	ENST00000397990.5
RNASE4	NM_002937.5	c.-17-5670A>G		intron_variant		ENST00000555835.3
EGILA	NR_174964.1	n.531T>C		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANG	ENST00000397990.5	c.121A>G	p.Lys41Glu	missense_variant	2/2	1	NM_001097577.3	P1
RNASE4	ENST00000555835.3	c.-17-5670A>G		intron_variant		1	NM_002937.5	P1
EGILA	ENST00000554286.1	n.710T>C		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Amyotrophic lateral sclerosis type 9 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	11
DANN	Benign	0.71
DEOGEN2	Benign	0.071	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.64	.;T
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.068	D
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.0000012	A;A;A;A;A
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.57
Sift	Benign	0.26	T;T
Sift4G	Benign	0.68	T;T
Polyphen		0.037	B;B
Vest4		0.16
MutPred		0.74		Gain of catalytic residue at H37 (P = 0.0058);Gain of catalytic residue at H37 (P = 0.0058);
MVP		0.91
MPC		0.35
ClinPred		0.16	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.57
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121909537; hg19: chr14-21161844;