chr14-20699417-A-T

Variant names:

• chr14-20699417-A-T
• rs3748338
• NM_002937.5:c.46A>T

Variant summary

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

The NM_002937.5(RNASE4):​c.46A>T​(p.Thr16Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,608,562 control chromosomes in the GnomAD database, including 18,511 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 0.12 (1245 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17266 hom.)
• Consequence: RNASE4 NM_002937.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 25 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]

ENSG00000259171 (HGNC:):

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018668771).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASE4	NM_002937.5	c.46A>T	p.Thr16Ser	missense_variant	Exon 2 of 2	ENST00000555835.3	NP_002928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASE4	ENST00000555835.3	c.46A>T	p.Thr16Ser	missense_variant	Exon 2 of 2	1	NM_002937.5	ENSP00000452245.1
ENSG00000259171	ENST00000553909.1	c.*53A>T		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000477037.1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17507 AN: 151830 Hom.: 1246 Cov.: 32

Gnomad AFR AF: 0.0280

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.146 AC: 36625 AN: 250066 AF XY: 0.153

Gnomad AFR exome AF: 0.0260

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.196

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.149 AC: 217739 AN: 1456614 Hom.: 17266 Cov.: 32 AF XY: 0.152 AC XY: 110300 AN XY: 723650

African (AFR) AF: 0.0231 AC: 771 AN: 33402

American (AMR) AF: 0.117 AC: 5219 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 4557 AN: 26022

East Asian (EAS) AF: 0.223 AC: 8819 AN: 39542

South Asian (SAS) AF: 0.219 AC: 18843 AN: 86134

European-Finnish (FIN) AF: 0.133 AC: 7003 AN: 52714

Middle Eastern (MID) AF: 0.166 AC: 953 AN: 5746

European-Non Finnish (NFE) AF: 0.147 AC: 162504 AN: 1108308

Other (OTH) AF: 0.151 AC: 9070 AN: 60132

GnomAD4 genome AF: 0.115 AC: 17506 AN: 151948 Hom.: 1245 Cov.: 32 AF XY: 0.118 AC XY: 8738 AN XY: 74254

African (AFR) AF: 0.0279 AC: 1157 AN: 41432

American (AMR) AF: 0.117 AC: 1780 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 573 AN: 3464

East Asian (EAS) AF: 0.211 AC: 1089 AN: 5150

South Asian (SAS) AF: 0.218 AC: 1051 AN: 4814

European-Finnish (FIN) AF: 0.144 AC: 1522 AN: 10542

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.146 AC: 9903 AN: 67952

Other (OTH) AF: 0.117 AC: 247 AN: 2112

Alfa AF: 0.131 Hom.: 946

Bravo AF: 0.108

TwinsUK AF: 0.141 AC: 522

ALSPAC AF: 0.143 AC: 552

ESP6500AA AF: 0.0320 AC: 141

ESP6500EA AF: 0.146 AC: 1256

ExAC AF: 0.145 AC: 17561

Asia WGS AF: 0.194 AC: 674 AN: 3478

EpiCase AF: 0.151

EpiControl AF: 0.148

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0033	T;T;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.50	.;.;T
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.6	M;M;M
PhyloP100		1.0
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.90	N;N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0030	D;D;D
Sift4G	Benign	0.38	T;T;T
Polyphen		0.97	D;D;D
Vest4		0.12
MutPred		0.23		Gain of catalytic residue at L12 (P = 0.0041);Gain of catalytic residue at L12 (P = 0.0041);Gain of catalytic residue at L12 (P = 0.0041);
MPC		0.30
ClinPred		0.029	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.38
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: rs3748338; hg19: chr14-21167576; COSMIC: COSV59011747; COSMIC: COSV59011747;