1-40515059-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001346953.2(EXO5):​c.515G>T​(p.Gly172Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,613,684 control chromosomes in the GnomAD database, including 132,479 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G172R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.47 (18211 hom., cov: 31)
  • Exomes 𝑓: 0.39 (114268 hom.)
• Consequence: EXO5 NM_001346953.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.4286504E-6).
• BP6: Variant 1-40515059-G-T is Benign according to our data. Variant chr1-40515059-G-T is described in ClinVar as Benign. ClinVar VariationId is 1252459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

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>T	p.Gly172Val	missense	Exon 4 of 4	NP_001333882.1	Q9H790
	EXO5	NM_001346946.2		c.515G>T	p.Gly172Val	missense	Exon 3 of 3	NP_001333875.1	Q9H790
	EXO5	NM_001346947.2		c.515G>T	p.Gly172Val	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>T	p.Gly172Val	missense	Exon 4 of 4	ENSP00000413565.2	Q9H790
	EXO5	ENST00000358527.6	TSL:1	c.515G>T	p.Gly172Val	missense	Exon 4 of 4	ENSP00000351328.2	Q9H790
	EXO5	ENST00000296380.9	TSL:2	c.515G>T	p.Gly172Val	missense	Exon 3 of 3	ENSP00000296380.4	Q9H790

Frequencies

GnomAD3 genomes AF: 0.471 AC: 71490 AN: 151802 Hom.: 18177 Cov.: 31

Gnomad AFR AF: 0.649

Gnomad AMI AF: 0.551

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.466

GnomAD2 exomes AF: 0.445 AC: 111916 AN: 251346 AF XY: 0.439

Gnomad AFR exome AF: 0.654

Gnomad AMR exome AF: 0.579

Gnomad ASJ exome AF: 0.467

Gnomad EAS exome AF: 0.489

Gnomad FIN exome AF: 0.348

Gnomad NFE exome AF: 0.363

Gnomad OTH exome AF: 0.433

GnomAD4 exome AF: 0.387 AC: 565933 AN: 1461764 Hom.: 114268 Cov.: 49 AF XY: 0.390 AC XY: 283754 AN XY: 727184

African (AFR) AF: 0.659 AC: 22069 AN: 33480

American (AMR) AF: 0.570 AC: 25481 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 12121 AN: 26134

East Asian (EAS) AF: 0.526 AC: 20879 AN: 39698

South Asian (SAS) AF: 0.527 AC: 45431 AN: 86252

European-Finnish (FIN) AF: 0.347 AC: 18502 AN: 53396

Middle Eastern (MID) AF: 0.521 AC: 3004 AN: 5764

European-Non Finnish (NFE) AF: 0.354 AC: 393099 AN: 1111922

Other (OTH) AF: 0.420 AC: 25347 AN: 60394

GnomAD4 genome AF: 0.471 AC: 71574 AN: 151920 Hom.: 18211 Cov.: 31 AF XY: 0.473 AC XY: 35101 AN XY: 74264

African (AFR) AF: 0.649 AC: 26886 AN: 41398

American (AMR) AF: 0.524 AC: 8004 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1606 AN: 3466

East Asian (EAS) AF: 0.495 AC: 2556 AN: 5162

South Asian (SAS) AF: 0.534 AC: 2572 AN: 4812

European-Finnish (FIN) AF: 0.348 AC: 3680 AN: 10568

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24647 AN: 67936

Other (OTH) AF: 0.464 AC: 979 AN: 2110

Alfa AF: 0.403 Hom.: 63591

Bravo AF: 0.491

TwinsUK AF: 0.360 AC: 1334

ALSPAC AF: 0.344 AC: 1325

ESP6500AA AF: 0.638 AC: 2811

ESP6500EA AF: 0.372 AC: 3196

ExAC AF: 0.444 AC: 53925

Asia WGS AF: 0.545 AC: 1898 AN: 3478

EpiCase AF: 0.373

EpiControl AF: 0.375

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.037
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Benign	0.81
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0000074	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-3.0	N
PhyloP100		2.1
PrimateAI	Benign	0.39	T
PROVEAN	Benign	4.2	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.071
MPC		0.18
ClinPred		0.0034	T
GERP RS		4.0
Varity_R		0.092
gMVP		0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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; COSMIC: COSV56415948; COSMIC: COSV56415948;