NM_017820.5:c.2540G>C

Variant names:

• chr9-137307041-C-G
• rs375831870
• NM_017820.5:c.2540G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017820.5(EXD3):​c.2540G>C​(p.Arg847Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R847H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EXD3 NM_017820.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.425
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

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.2540G>C	p.Arg847Pro	missense	Exon 22 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.2540G>C	p.Arg847Pro	missense	Exon 22 of 22	ENSP00000340474.4	Q8N9H8-1
	EXD3	ENST00000491734.6	TSL:1	n.*1608G>C		non_coding_transcript_exon	Exon 15 of 15	ENSP00000435830.1	E9PSB6
	EXD3	ENST00000491734.6	TSL:1	n.*1608G>C		3_prime_UTR	Exon 15 of 15	ENSP00000435830.1	E9PSB6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460030 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726302

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111654

Other (OTH) AF: 0.00 AC: 0 AN: 60338

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.42
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.023	D
Polyphen		0.49	P
Vest4		0.66
MutPred		0.77		Gain of loop (P = 0.0166)
MVP		0.32
MPC		0.41
ClinPred		0.90	D
GERP RS		1.2
Varity_R		0.35
gMVP		0.84
Mutation Taster		=93/7	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: rs375831870; hg19: chr9-140201493;