NM_014285.7:c.16A>T

Variant names:

• chr9-130693807-A-T
• rs1259246653
• NM_014285.7:c.16A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014285.7(EXOSC2):​c.16A>T​(p.Arg6Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,454,760 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R6R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: EXOSC2 NM_014285.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.503
• Publications: 0 publications found

Genes affected

EXOSC2 (HGNC:17097): (exosome component 2) Predicted to enable RNA binding activity. Involved in positive regulation of cell growth. Located in cytoplasm; nucleolus; and nucleoplasm. Part of nuclear exosome (RNase complex). [provided by Alliance of Genome Resources, Apr 2022]

EXOSC2 Gene-Disease associations (from GenCC):

• retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014285.7. 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
	EXOSC2	NM_014285.7	MANE Select	c.16A>T	p.Arg6Trp	missense	Exon 1 of 9	NP_055100.2
	EXOSC2	NM_001282708.1		c.16A>T	p.Arg6Trp	missense	Exon 1 of 8	NP_001269637.1	Q13868-2
	EXOSC2	NM_001282709.1		c.16A>T	p.Arg6Trp	missense	Exon 1 of 8	NP_001269638.1	Q13868-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC2	ENST00000372358.10	TSL:1 MANE Select	c.16A>T	p.Arg6Trp	missense	Exon 1 of 9	ENSP00000361433.5	Q13868-1
	EXOSC2	ENST00000851443.1		c.16A>T	p.Arg6Trp	missense	Exon 1 of 10	ENSP00000521502.1
	EXOSC2	ENST00000495699.3	TSL:3	c.16A>T	p.Arg6Trp	missense	Exon 1 of 8	ENSP00000418463.3	A3KFL5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1454760 Hom.: 0 Cov.: 33 AF XY: 0.00000691 AC XY: 5 AN XY: 723696

African (AFR) AF: 0.00 AC: 0 AN: 33234

American (AMR) AF: 0.00 AC: 0 AN: 44220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39292

South Asian (SAS) AF: 0.00 AC: 0 AN: 85976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000542 AC: 6 AN: 1107166

Other (OTH) AF: 0.00 AC: 0 AN: 59944

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.028
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.50
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.73
MutPred		0.53		Loss of disorder (P = 0)
MVP		0.50
MPC		0.88
ClinPred		1.0	D
GERP RS		-1.1
PromoterAI		-0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.81
Mutation Taster		=65/35	polymorphism

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: rs1259246653; hg19: chr9-133569194;