9-137309664-C-A

Variant names:

• chr9-137309664-C-A
• rs1158927150
• NM_017820.5:c.2221G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017820.5(EXD3):​c.2221G>T​(p.Asp741Tyr) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EXD3 NM_017820.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86
• Publications: 0 publications found

Genes affected

EXD3 (HGNC:26023): (exonuclease 3'-5' domain containing 3) Predicted to enable 3'-5' exonuclease activity. Predicted to be involved in nucleic acid phosphodiester bond hydrolysis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26263452).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017820.5. 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
	EXD3	NM_017820.5	MANE Select	c.2221G>T	p.Asp741Tyr	missense	Exon 20 of 22	NP_060290.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXD3	ENST00000340951.9	TSL:1 MANE Select	c.2221G>T	p.Asp741Tyr	missense	Exon 20 of 22	ENSP00000340474.4	Q8N9H8-1
	EXD3	ENST00000491734.6	TSL:1	n.*1328G>T		non_coding_transcript_exon	Exon 14 of 15	ENSP00000435830.1	E9PSB6
	EXD3	ENST00000491734.6	TSL:1	n.*1328G>T		3_prime_UTR	Exon 14 of 15	ENSP00000435830.1	E9PSB6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1407754 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 695298

African (AFR) AF: 0.00 AC: 0 AN: 32020

American (AMR) AF: 0.00 AC: 0 AN: 36924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25354

East Asian (EAS) AF: 0.00 AC: 0 AN: 36544

South Asian (SAS) AF: 0.00 AC: 0 AN: 79804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084084

Other (OTH) AF: 0.00 AC: 0 AN: 58428

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.9
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.23
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.34
MutPred		0.54		Loss of ubiquitination at K744 (P = 0.0234)
MVP		0.36
MPC		0.38
ClinPred		0.94	D
GERP RS		2.6
Varity_R		0.12
gMVP		0.62
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1158927150; hg19: chr9-140204116;