1-40515059-G-C

Variant names:

• chr1-40515059-G-C
• rs11208299
• NM_001346953.2:c.515G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001346953.2(EXO5):​c.515G>C​(p.Gly172Ala) 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. 16/22 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. G172V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EXO5 NM_001346953.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.14
• Publications: 37 publications found

Genes affected

EXO5 (HGNC:26115): (exonuclease 5) The protein encoded by this gene is a single-stranded DNA (ssDNA)-specific exonuclease that can slide along the DNA before cutting it. However, human replication protein A binds ssDNA and restricts sliding of the encoded protein, providing a 5'-directionality to the enzyme. This protein localizes to nuclear repair loci after DNA damage. [provided by RefSeq, Nov 2016]

ENSG00000227278 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053926617).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346953.2. 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
	EXO5	NM_001346953.2	MANE Select	c.515G>C	p.Gly172Ala	missense	Exon 4 of 4	NP_001333882.1	Q9H790
	EXO5	NM_001346946.2		c.515G>C	p.Gly172Ala	missense	Exon 3 of 3	NP_001333875.1	Q9H790
	EXO5	NM_001346947.2		c.515G>C	p.Gly172Ala	missense	Exon 4 of 4	NP_001333876.1	Q9H790

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXO5	ENST00000415550.6	TSL:2 MANE Select	c.515G>C	p.Gly172Ala	missense	Exon 4 of 4	ENSP00000413565.2	Q9H790
	EXO5	ENST00000358527.6	TSL:1	c.515G>C	p.Gly172Ala	missense	Exon 4 of 4	ENSP00000351328.2	Q9H790
	EXO5	ENST00000296380.9	TSL:2	c.515G>C	p.Gly172Ala	missense	Exon 3 of 3	ENSP00000296380.4	Q9H790

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 49

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.0015	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.81	N
PhyloP100		2.1
PrimateAI	Benign	0.42	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.086
Sift	Benign	0.50	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.50		Loss of relative solvent accessibility (P = 0.0071)
MVP		0.072
MPC		0.16
ClinPred		0.11	T
GERP RS		4.0
Varity_R		0.056
gMVP		0.30
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11208299; hg19: chr1-40980731;