14-20693927-A-T

Variant names:

• chr14-20693927-A-T
• rs2228653
• NM_001097577.3:c.363A>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001145.4(ANG):​c.363A>T​(p.Thr121Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00296 in 1,614,146 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (53 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (38 hom.)
• Consequence: ANG NM_001145.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.827
• Publications: 5 publications found

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]

ENSG00000259171 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 14-20693927-A-T is Benign according to our data. Variant chr14-20693927-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 312775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.827 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0141 (2145/152254) while in subpopulation AFR AF = 0.0457 (1898/41534). AF 95% confidence interval is 0.044. There are 53 homozygotes in GnomAd4. There are 1016 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2145 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANG	NM_001097577.3	MANE Select	c.363A>T	p.Thr121Thr	synonymous	Exon 2 of 2	NP_001091046.1
	RNASE4	NM_002937.5	MANE Select	c.-17-5428A>T		intron	N/A	NP_002928.1
	ANG	NM_001145.4		c.363A>T	p.Thr121Thr	synonymous	Exon 2 of 2	NP_001136.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANG	ENST00000397990.5	TSL:1 MANE Select	c.363A>T	p.Thr121Thr	synonymous	Exon 2 of 2	ENSP00000381077.4
	ANG	ENST00000336811.10	TSL:1	c.363A>T	p.Thr121Thr	synonymous	Exon 2 of 2	ENSP00000336762.6
	RNASE4	ENST00000555835.3	TSL:1 MANE Select	c.-17-5428A>T		intron	N/A	ENSP00000452245.1

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2133 AN: 152136 Hom.: 54 Cov.: 32

Gnomad AFR AF: 0.0456

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00412 AC: 1035 AN: 251492 AF XY: 0.00314

Gnomad AFR exome AF: 0.0476

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000765

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00180 AC: 2635 AN: 1461892 Hom.: 38 Cov.: 32 AF XY: 0.00159 AC XY: 1157 AN XY: 727248

African (AFR) AF: 0.0441 AC: 1477 AN: 33480

American (AMR) AF: 0.00501 AC: 224 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26136

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

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86258

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

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5768

European-Non Finnish (NFE) AF: 0.000506 AC: 563 AN: 1112010

Other (OTH) AF: 0.00457 AC: 276 AN: 60396

GnomAD4 genome AF: 0.0141 AC: 2145 AN: 152254 Hom.: 53 Cov.: 32 AF XY: 0.0136 AC XY: 1016 AN XY: 74460

African (AFR) AF: 0.0457 AC: 1898 AN: 41534

American (AMR) AF: 0.0105 AC: 160 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68010

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.0168

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.00148

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Amyotrophic lateral sclerosis type 9 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.18
DANN	Benign	0.76
PhyloP100		-0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs2228653; hg19: chr14-21162086;