14-20684736-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002937.5(RNASE4):c.-40T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 152,678 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.025 (66 hom., cov: 32)
  • Exomes 𝑓: 0.022 (0 hom.)
• Consequence: RNASE4 NM_002937.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.483

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 14-20684736-T-C is Benign according to our data. Variant chr14-20684736-T-C is described in ClinVar as [Benign]. Clinvar id is 312771.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0253 (3860/152320) while in subpopulation SAS AF= 0.0422 (204/4830). AF 95% confidence interval is 0.0375. There are 66 homozygotes in gnomad4. There are 2036 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 66 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASE4	NM_002937.5	c.-40T>C		5_prime_UTR_variant	1/2	ENST00000555835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASE4	ENST00000555835.3	c.-40T>C		5_prime_UTR_variant	1/2	1	NM_002937.5	P1
ANG	ENST00000336811.10	c.-41T>C		5_prime_UTR_variant	1/2	1		P1
RNASE4	ENST00000397995.2	c.-18+40T>C		intron_variant		2		P1
ANG	ENST00000554073.1	n.123T>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3861 AN: 152202 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.00606

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0426

Gnomad FIN AF: 0.0673

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0328

Gnomad OTH AF: 0.0282

GnomAD4 exome AF: 0.0223 AC: 8 AN: 358 Hom.: 0 Cov.: 0 AF XY: 0.0254 AC XY: 7 AN XY: 276

Gnomad4 AFR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0556

Gnomad4 NFE exome AF: 0.0240

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0253 AC: 3860 AN: 152320 Hom.: 66 Cov.: 32 AF XY: 0.0273 AC XY: 2036 AN XY: 74488

Gnomad4 AFR AF: 0.00606

Gnomad4 AMR AF: 0.0207

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0422

Gnomad4 FIN AF: 0.0673

Gnomad4 NFE AF: 0.0328

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0295 Hom.: 19

Bravo AF: 0.0199

Asia WGS AF: 0.0230 AC: 80 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	8.3
Dann	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs117978329; hg19: chr14-21152895;