4-121801378-G-A

Variant names:

• chr4-121801378-G-A
• rs115766017
• NM_005033.3:c.-47G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005033.3(EXOSC9):​c.-47G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,581,396 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (86 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (76 hom.)
• Consequence: EXOSC9 NM_005033.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.51
• Publications: 1 publications found

Genes affected

EXOSC9 (HGNC:9137): (exosome component 9) This gene encodes a component of the human exosome, a exoribonuclease complex which processes and degrades RNA in the nucleus and cytoplasm. This component may play a role in mRNA degradation and the polymyositis/scleroderma autoantigen complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

EXOSC9 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia, type 1D

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pontocerebellar hypoplasia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 4-121801378-G-A is Benign according to our data. Variant chr4-121801378-G-A is described in ClinVar as Benign. ClinVar VariationId is 1268353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005033.3. 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
	EXOSC9	NM_005033.3	MANE Select	c.-47G>A		5_prime_UTR	Exon 1 of 12	NP_005024.2	Q06265-1
	EXOSC9	NM_001034194.2		c.-47G>A		5_prime_UTR	Exon 1 of 13	NP_001029366.1	Q06265-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC9	ENST00000243498.10	TSL:1 MANE Select	c.-47G>A		5_prime_UTR	Exon 1 of 12	ENSP00000243498.5	Q06265-1
	EXOSC9	ENST00000379663.7	TSL:1	c.-47G>A		5_prime_UTR	Exon 1 of 13	ENSP00000368984.3	Q06265-2
	EXOSC9	ENST00000940329.1		c.-47G>A		5_prime_UTR	Exon 1 of 13	ENSP00000610388.1

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2440 AN: 152200 Hom.: 85 Cov.: 33

Gnomad AFR AF: 0.0563

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00404 AC: 1013 AN: 250988 AF XY: 0.00305

Gnomad AFR exome AF: 0.0553

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.00172 AC: 2457 AN: 1429078 Hom.: 76 Cov.: 26 AF XY: 0.00151 AC XY: 1076 AN XY: 713028

African (AFR) AF: 0.0604 AC: 1983 AN: 32826

American (AMR) AF: 0.00273 AC: 122 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39508

South Asian (SAS) AF: 0.000164 AC: 14 AN: 85572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53280

Middle Eastern (MID) AF: 0.00474 AC: 27 AN: 5694

European-Non Finnish (NFE) AF: 0.0000933 AC: 101 AN: 1082396

Other (OTH) AF: 0.00354 AC: 210 AN: 59246

GnomAD4 genome AF: 0.0161 AC: 2449 AN: 152318 Hom.: 86 Cov.: 33 AF XY: 0.0156 AC XY: 1161 AN XY: 74492

African (AFR) AF: 0.0564 AC: 2342 AN: 41554

American (AMR) AF: 0.00451 AC: 69 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68034

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00655 Hom.: 12

Bravo AF: 0.0179

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.4
DANN	Benign	0.88
PhyloP100		-2.5
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

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

dbSNP: rs115766017; hg19: chr4-122722533;