14-20685140-A-C

Variant names:

• chr14-20685140-A-C
• rs9322855
• NM_002937.5:c.-18+382A>C

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+382A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 151,848 control chromosomes in the GnomAD database, including 15,468 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 0.45 (15468 hom., cov: 31)
• Consequence: RNASE4 NM_002937.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.199
• Publications: 27 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=-0.66).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.501 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASE4	NM_002937.5	MANE Select	c.-18+382A>C		intron	N/A	NP_002928.1
	ANG	NM_001145.4		c.-19+382A>C		intron	N/A	NP_001136.1
	RNASE4	NM_001282192.2		c.-122+382A>C		intron	N/A	NP_001269121.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASE4	ENST00000555835.3	TSL:1 MANE Select	c.-18+382A>C		intron	N/A	ENSP00000452245.1
	ANG	ENST00000336811.10	TSL:1	c.-19+382A>C		intron	N/A	ENSP00000336762.6
	ENSG00000259171	ENST00000553909.1	TSL:2	c.-19+382A>C		intron	N/A	ENSP00000477037.1

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68145 AN: 151730 Hom.: 15451 Cov.: 31

Gnomad AFR AF: 0.507

Gnomad AMI AF: 0.535

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.446

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.442

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

GnomAD4 genome AF: 0.449 AC: 68209 AN: 151848 Hom.: 15468 Cov.: 31 AF XY: 0.447 AC XY: 33169 AN XY: 74194

African (AFR) AF: 0.507 AC: 20972 AN: 41370

American (AMR) AF: 0.407 AC: 6215 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 1661 AN: 3470

East Asian (EAS) AF: 0.447 AC: 2299 AN: 5144

South Asian (SAS) AF: 0.393 AC: 1893 AN: 4818

European-Finnish (FIN) AF: 0.388 AC: 4087 AN: 10536

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.434 AC: 29514 AN: 67928

Other (OTH) AF: 0.439 AC: 929 AN: 2116

Alfa AF: 0.441 Hom.: 25750

Bravo AF: 0.457

Asia WGS AF: 0.401 AC: 1394 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.1
DANN	Benign	0.83
PhyloP100		-0.20
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: rs9322855; hg19: chr14-21153299;