19-41389881-C-T

Variant names:

• chr19-41389881-C-T
• rs376614222
• NM_020158.4:c.409G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020158.4(EXOSC5):​c.409G>A​(p.Ala137Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,611,100 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 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: EXOSC5 NM_020158.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.84

Genes affected

EXOSC5 (HGNC:24662): (exosome component 5) Predicted to enable RNA binding activity. Involved in DNA deamination and exonucleolytic catabolism of deadenylated mRNA. Acts upstream of or within defense response to virus. Located in nucleolus; nucleoplasm; and transcriptionally active chromatin. Part of exosome (RNase complex). [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000255730 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045786172).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC5	NM_020158.4	c.409G>A	p.Ala137Thr	missense_variant	Exon 4 of 6	ENST00000221233.9	NP_064543.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOSC5	ENST00000221233.9	c.409G>A	p.Ala137Thr	missense_variant	Exon 4 of 6	1	NM_020158.4	ENSP00000221233.3
ENSG00000255730	ENST00000540732.3	c.210+11362C>T		intron_variant	Intron 2 of 9	2		ENSP00000443246.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152020 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000223 AC: 55 AN: 246752 Hom.: 0 AF XY: 0.000254 AC XY: 34 AN XY: 133628

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.0000893

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00188

Gnomad SAS exome AF: 0.000266

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000806

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000113 AC: 165 AN: 1458966 Hom.: 0 Cov.: 30 AF XY: 0.000110 AC XY: 80 AN XY: 725900

Gnomad4 AFR exome AF: 0.0000904

Gnomad4 AMR exome AF: 0.0000681

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00124

Gnomad4 SAS exome AF: 0.000314

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000639

Gnomad4 OTH exome AF: 0.000183

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152134 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74352

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000253 Hom.: 0

Bravo AF: 0.000196

ExAC AF: 0.000165 AC: 20

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.409G>A (p.A137T) alteration is located in exon 4 (coding exon 4) of the EXOSC5 gene. This alteration results from a G to A substitution at nucleotide position 409, causing the alanine (A) at amino acid position 137 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Jun 28, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.046	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Uncertain	0.36
Sift	Benign	0.056	T;.
Sift4G	Benign	0.087	T;D
Polyphen		1.0	D;.
Vest4		0.49
MVP		0.45
MPC		0.22
ClinPred		0.15	T
GERP RS		2.9
Varity_R		0.52
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs376614222; hg19: chr19-41895786;