rs201468947

Variant names:

• chr19-41387596-C-T
• rs201468947
• NM_020158.4:c.533G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-41387596-C-T
• chr19-41387596-C-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_020158.4(EXOSC5):​c.533G>A​(p.Arg178Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,597,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: EXOSC5 NM_020158.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.38
• Publications: 1 publications found

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]

EXOSC5 Gene-Disease associations (from GenCC):

• cerebellar ataxia, brain abnormalities, and cardiac conduction defects

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000255730 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.033602387).
• BP6: Variant 19-41387596-C-T is Benign according to our data. Variant chr19-41387596-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1879440.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020158.4. 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
	EXOSC5	NM_020158.4	MANE Select	c.533G>A	p.Arg178Gln	missense	Exon 5 of 6	NP_064543.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC5	ENST00000221233.9	TSL:1 MANE Select	c.533G>A	p.Arg178Gln	missense	Exon 5 of 6	ENSP00000221233.3	Q9NQT4
	ENSG00000255730	ENST00000540732.3	TSL:2	c.210+9077C>T		intron	N/A	ENSP00000443246.1	F5H5P2
	EXOSC5	ENST00000593771.2	TSL:3	c.599G>A	p.Arg200Gln	missense	Exon 6 of 7	ENSP00000471557.2	M0R102

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 151954 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000263

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: 0.0000441

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000167 AC: 37 AN: 221372 AF XY: 0.000218

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000297

Gnomad ASJ exome AF: 0.000109

Gnomad EAS exome AF: 0.0000604

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000367

GnomAD4 exome AF: 0.000131 AC: 190 AN: 1445332 Hom.: 0 Cov.: 30 AF XY: 0.000130 AC XY: 93 AN XY: 717734

African (AFR) AF: 0.00 AC: 0 AN: 33074

American (AMR) AF: 0.000387 AC: 16 AN: 41382

Ashkenazi Jewish (ASJ) AF: 0.0000392 AC: 1 AN: 25536

East Asian (EAS) AF: 0.0000511 AC: 2 AN: 39148

South Asian (SAS) AF: 0.000457 AC: 38 AN: 83138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52532

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5724

European-Non Finnish (NFE) AF: 0.0000941 AC: 104 AN: 1105076

Other (OTH) AF: 0.000335 AC: 20 AN: 59722

GnomAD4 genome AF: 0.0000987 AC: 15 AN: 151954 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74200

African (AFR) AF: 0.0000242 AC: 1 AN: 41356

American (AMR) AF: 0.000263 AC: 4 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67980

Other (OTH) AF: 0.000958 AC: 2 AN: 2088

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.000340

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000140 AC: 17

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T
Eigen	Benign	0.083
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.4
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.10
Sift	Benign	0.11	T
Sift4G	Benign	0.28	T
Polyphen		0.24	B
Vest4		0.31
MutPred		0.38		Gain of methylation at K175 (P = 0.0482)
MVP		0.19
MPC		0.24
ClinPred		0.025	T
GERP RS		5.3
Varity_R		0.27
gMVP		0.57
Mutation Taster		=64/36	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

Other links and lift over

dbSNP: rs201468947; hg19: chr19-41893501; COSMIC: COSV55371433; COSMIC: COSV55371433;