chr15-66311850-C-G

Variant names:

• chr15-66311850-C-G
• rs373895810
• NM_001143688.3:c.685C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001323940.2(DIS3L):​c.-256C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: DIS3L NM_001323940.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00
• Publications: 1 publications found

Genes affected

DIS3L (HGNC:28698): (DIS3 like exosome 3'-5' exoribonuclease) The cytoplasmic RNA exosome complex degrades unstable mRNAs and is involved in the regular turnover of other mRNAs. The protein encoded by this gene contains 3'-5' exoribonuclease activity and is a catalytic component of this complex. [provided by RefSeq, May 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16301957).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323940.2. 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
	DIS3L	NM_001143688.3	MANE Select	c.685C>G	p.Leu229Val	missense	Exon 5 of 17	NP_001137160.1	Q8TF46-1
	DIS3L	NM_001323940.2		c.-256C>G		5_prime_UTR_premature_start_codon_gain	Exon 5 of 16	NP_001310869.1
	DIS3L	NM_001323943.2		c.-256C>G		5_prime_UTR_premature_start_codon_gain	Exon 5 of 16	NP_001310872.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L	ENST00000319212.9	TSL:5 MANE Select	c.685C>G	p.Leu229Val	missense	Exon 5 of 17	ENSP00000321711.4	Q8TF46-1
	DIS3L	ENST00000319194.9	TSL:1	c.436C>G	p.Leu146Val	missense	Exon 5 of 17	ENSP00000321583.5	Q8TF46-4
	DIS3L	ENST00000530537.1	TSL:1	n.*195C>G		non_coding_transcript_exon	Exon 4 of 16	ENSP00000432407.1	E9PKI7

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152136 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.000281 AC: 17 AN: 60396

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152254 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74450

African (AFR) AF: 0.00 AC: 0 AN: 41538

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.83
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.12
Sift	Benign	0.067	T
Sift4G	Benign	0.064	T
Polyphen		0.0090	B
Vest4		0.38
MutPred		0.34		Loss of catalytic residue at L229 (P = 0.1638)
MVP		0.69
MPC		0.18
ClinPred		0.26	T
GERP RS		4.1
Varity_R		0.12
gMVP		0.50
Mutation Taster		=87/13	polymorphism

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: rs373895810; hg19: chr15-66604188; COSMIC: COSV100055062; COSMIC: COSV100055062;