15-66318553-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001143688.3(DIS3L):c.1099G>A(p.Val367Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DIS3L NM_001143688.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2493164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIS3L	NM_001143688.3	c.1099G>A	p.Val367Ile	missense_variant	8/17	ENST00000319212.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIS3L	ENST00000319212.9	c.1099G>A	p.Val367Ile	missense_variant	8/17	5	NM_001143688.3	P1
	ENST00000565993.1	n.295-3434C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2022

The c.1099G>A (p.V367I) alteration is located in exon 8 (coding exon 8) of the DIS3L gene. This alteration results from a G to A substitution at nucleotide position 1099, causing the valine (V) at amino acid position 367 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.065
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.80	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.36	N;N
REVEL	Benign	0.13
Sift	Benign	0.099	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.022	.;B
Vest4		0.34
MutPred		0.47		.;Gain of catalytic residue at P369 (P = 0.0482);
MVP		0.47
MPC		0.15
ClinPred		0.56	D
GERP RS		4.0
Varity_R		0.082
gMVP		0.30

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: rs375710056; hg19: chr15-66610891;