19-41386638-T-C

Position:

• chr19-41386638-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020158.4(EXOSC5):​c.703A>G​(p.Ser235Gly) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXOSC5 NM_020158.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15964982).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXOSC5	NM_020158.4	c.703A>G	p.Ser235Gly	missense_variant	6/6	ENST00000221233.9	NP_064543.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOSC5	ENST00000221233.9	c.703A>G	p.Ser235Gly	missense_variant	6/6	1	NM_020158.4	ENSP00000221233	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.703A>G (p.S235G) alteration is located in exon 6 (coding exon 6) of the EXOSC5 gene. This alteration results from a A to G substitution at nucleotide position 703, causing the serine (S) at amino acid position 235 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	0.68	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.052
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.015	D;D
Polyphen		0.91	P;.
Vest4		0.34
MutPred		0.33		Loss of phosphorylation at S235 (P = 0.0061);.;
MVP		0.11
MPC		0.21
ClinPred		0.61	D
GERP RS		5.1
Varity_R		0.28
gMVP		0.48

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-41892543;