NM_002937.5:c.-18+3274G>A

Variant names:

• chr14-20688032-G-A
• rs4470055
• NM_002937.5:c.-18+3274G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002937.5(RNASE4):​c.-18+3274G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 152,050 control chromosomes in the GnomAD database, including 8,856 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (8856 hom., cov: 32)
• Consequence: RNASE4 NM_002937.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• Publications: 19 publications found

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]

ANG Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 9

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000259171 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002937.5. 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
	RNASE4	NM_002937.5	MANE Select	c.-18+3274G>A		intron	N/A	NP_002928.1
	ANG	NM_001145.4		c.-19+3274G>A		intron	N/A	NP_001136.1
	RNASE4	NM_001282192.2		c.-122+3274G>A		intron	N/A	NP_001269121.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASE4	ENST00000555835.3	TSL:1 MANE Select	c.-18+3274G>A		intron	N/A	ENSP00000452245.1
	ANG	ENST00000336811.10	TSL:1	c.-19+3274G>A		intron	N/A	ENSP00000336762.6
	ENSG00000259171	ENST00000553909.1	TSL:2	c.-19+3274G>A		intron	N/A	ENSP00000477037.1

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49878 AN: 151932 Hom.: 8841 Cov.: 32

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.358

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.312

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.328 AC: 49935 AN: 152050 Hom.: 8856 Cov.: 32 AF XY: 0.329 AC XY: 24479 AN XY: 74310

African (AFR) AF: 0.470 AC: 19491 AN: 41468

American (AMR) AF: 0.252 AC: 3844 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 976 AN: 3470

East Asian (EAS) AF: 0.417 AC: 2159 AN: 5172

South Asian (SAS) AF: 0.277 AC: 1334 AN: 4816

European-Finnish (FIN) AF: 0.284 AC: 2999 AN: 10544

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 18047 AN: 67986

Other (OTH) AF: 0.311 AC: 655 AN: 2108

Alfa AF: 0.272 Hom.: 10809

Bravo AF: 0.334

Asia WGS AF: 0.310 AC: 1076 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.22
DANN	Benign	0.44
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs4470055; hg19: chr14-21156191; COSMIC: COSV59013158; COSMIC: COSV59013158;