rs782300876

Variant names:

• chr9-133407005-C-G
• rs782300876
• NM_020385.4:c.1217G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-133407005-C-G
• chr9-133407005-C-T

Variant summary

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

The NM_020385.4(REXO4):​c.1217G>C​(p.Arg406Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. R406Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: REXO4 NM_020385.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.11
• Publications: 0 publications found

Genes affected

REXO4 (HGNC:12820): (REX4 homolog, 3'-5' exonuclease) Enables DNA binding activity and nuclease activity. Involved in DNA catabolic process, endonucleolytic; DNA catabolic process, exonucleolytic; and DNA repair. Located in nuclear speck and nucleolus. [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=0.15926054).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020385.4. 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
	REXO4	NM_020385.4	MANE Select	c.1217G>C	p.Arg406Pro	missense	Exon 8 of 8	NP_065118.2	Q9GZR2-1
	REXO4	NM_001279351.1		c.938G>C	p.Arg313Pro	missense	Exon 8 of 8	NP_001266280.1	Q9GZR2
	REXO4	NM_001279350.2		c.806G>C	p.Arg269Pro	missense	Exon 8 of 8	NP_001266279.1	B4E331

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REXO4	ENST00000371942.8	TSL:1 MANE Select	c.1217G>C	p.Arg406Pro	missense	Exon 8 of 8	ENSP00000361010.3	Q9GZR2-1
	REXO4	ENST00000903994.1		c.1241G>C	p.Arg414Pro	missense	Exon 8 of 8	ENSP00000574053.1
	REXO4	ENST00000903993.1		c.1235G>C	p.Arg412Pro	missense	Exon 8 of 8	ENSP00000574052.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460938 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726802

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		-1.1
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.061
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.090
MutPred		0.55		Loss of MoRF binding (P = 7e-04)
MVP		0.21
MPC		0.32
ClinPred		0.72	D
GERP RS		-3.6
Varity_R		0.16
gMVP		0.63
Mutation Taster		=75/25	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: rs782300876; hg19: chr9-136272129;