rs3748338

chr14-20699417-A-Cchr14-20699417-A-Gchr14-20699417-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002937.5(RNASE4):c.46A>C(p.Thr16Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000618 in 1,456,724 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T16S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: RNASE4 NM_002937.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASE4	NM_002937.5	c.46A>C	p.Thr16Pro	missense_variant	2/2	ENST00000555835.3
EGILA	NR_174964.1	n.277T>G		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASE4	ENST00000555835.3	c.46A>C	p.Thr16Pro	missense_variant	2/2	1	NM_002937.5	P1
EGILA	ENST00000554286.1	n.456T>G		non_coding_transcript_exon_variant	2/4	5
RNASE4	ENST00000397995.2	c.46A>C	p.Thr16Pro	missense_variant	2/2	2		P1
RNASE4	ENST00000555597.1	c.46A>C	p.Thr16Pro	missense_variant	2/2	2		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000618 AC: 9 AN: 1456724 Hom.: 0 Cov.: 32 AF XY: 0.00000415 AC XY: 3 AN XY: 723712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000812

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0067	T;T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.74	D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	0.95	P;P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.33	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.46
MutPred		0.63		Gain of catalytic residue at L15 (P = 0.0011);Gain of catalytic residue at L15 (P = 0.0011);Gain of catalytic residue at L15 (P = 0.0011);
MVP		0.80
MPC		0.52
ClinPred		0.84	D
GERP RS		4.1
Varity_R		0.38
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs3748338; hg19: chr14-21167576;