15-66293690-C-T

Variant names:

• chr15-66293690-C-T
• NM_001143688.3:c.94C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001143688.3(DIS3L):​c.94C>T​(p.Pro32Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000161 in 1,245,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: DIS3L NM_001143688.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53
• Publications: 0 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]

DIS3L-AS1 (HGNC:55369): (DIS3L antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4070821).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143688.3. 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.94C>T	p.Pro32Ser	missense	Exon 1 of 17	NP_001137160.1	Q8TF46-1
	DIS3L	NM_001323938.2		c.-236C>T		5_prime_UTR	Exon 1 of 17	NP_001310867.1	Q8TF46-2
	DIS3L	NM_001323939.2		c.-433C>T		5_prime_UTR	Exon 1 of 18	NP_001310868.1	Q8TF46-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L	ENST00000319212.9	TSL:5 MANE Select	c.94C>T	p.Pro32Ser	missense	Exon 1 of 17	ENSP00000321711.4	Q8TF46-1
	DIS3L	ENST00000319194.9	TSL:1	c.-111+323C>T		intron	N/A	ENSP00000321583.5	Q8TF46-4
	DIS3L	ENST00000904294.1		c.94C>T	p.Pro32Ser	missense	Exon 1 of 17	ENSP00000574353.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000161 AC: 2 AN: 1245726 Hom.: 0 Cov.: 30 AF XY: 0.00000326 AC XY: 2 AN XY: 613230

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25518

American (AMR) AF: 0.00 AC: 0 AN: 23402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20776

East Asian (EAS) AF: 0.00 AC: 0 AN: 25348

South Asian (SAS) AF: 0.0000156 AC: 1 AN: 64126

European-Finnish (FIN) AF: 0.0000330 AC: 1 AN: 30258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3492

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1002878

Other (OTH) AF: 0.00 AC: 0 AN: 49928

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

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	0.16
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.050
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.86	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.10
Sift	Benign	0.19	T
Sift4G	Benign	0.52	T
Polyphen		0.26	B
Vest4		0.41
MutPred		0.70		Gain of MoRF binding (P = 0.2997)
MVP		0.40
MPC		0.23
ClinPred		0.72	D
GERP RS		4.9
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.14
gMVP		0.50

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

hg19: chr15-66586028;