NM_152383.5:c.2271C>A

Variant names:

• chr2-232334481-C-A
• NM_152383.5:c.2271C>A
• DIS3L2 p.Phe757Leu

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152383.5(DIS3L2):​c.2271C>A​(p.Phe757Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.10
• Publications: 0 publications found

Genes affected

DIS3L2 (HGNC:28648): (DIS3 like 3'-5' exoribonuclease 2) The protein encoded by this gene is similar in sequence to 3'/5' exonucleolytic subunits of the RNA exosome. The exosome is a large multimeric ribonucleotide complex responsible for degrading various RNA substrates. Several transcript variants, some protein-coding and some not, have been found for this gene. [provided by RefSeq, Mar 2012]

DIS3L2 Gene-Disease associations (from GenCC):

• Perlman syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152383.5. 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
	DIS3L2	NM_152383.5	MANE Select	c.2271C>A	p.Phe757Leu	missense	Exon 18 of 21	NP_689596.4
	DIS3L2	NM_001257281.2		c.1582-8864C>A		intron	N/A	NP_001244210.1	Q8IYB7-3
	DIS3L2	NR_046476.2		n.2344C>A		non_coding_transcript_exon	Exon 18 of 21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.2271C>A	p.Phe757Leu	missense	Exon 18 of 21	ENSP00000315569.7	Q8IYB7-1
	DIS3L2	ENST00000390005.9	TSL:1	n.*338C>A		non_coding_transcript_exon	Exon 18 of 21	ENSP00000374655.5	Q8IYB7-2
	DIS3L2	ENST00000445090.5	TSL:1	n.*1427C>A		non_coding_transcript_exon	Exon 17 of 19	ENSP00000388999.1	Q8IYB7-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	0.0095	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.056
Eigen_PC	Benign	0.037
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.022	D
PromoterAI		-0.055	Neutral
Varity_R		0.59
gMVP		0.80
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-233199191;