rs1635517

Positions:

• chr1-241848731-G-A
• chr1-241848731-G-C
• chr1-241848731-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_130398.4(EXO1):​c.-419G>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.618 in 151,876 control chromosomes in the GnomAD database, including 29,554 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.62 (29551 hom., cov: 31)
  • Exomes 𝑓: 0.61 (3 hom.)
• Consequence: EXO1 NM_130398.4 splice_region
• Scores: Splicing: ADA: 0.0001452
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0910

Genes affected

EXO1 (HGNC:3511): (exonuclease 1) This gene encodes a protein with 5' to 3' exonuclease activity as well as an RNase H activity. It is similar to the Saccharomyces cerevisiae protein Exo1 which interacts with Msh2 and which is involved in mismatch repair and recombination. Alternative splicing of this gene results in three transcript variants encoding two different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXO1	NM_130398.4	c.-419G>A		splice_region_variant	2/16	ENST00000366548.8	NP_569082.2
EXO1	NM_130398.4	c.-419G>A		5_prime_UTR_variant	2/16	ENST00000366548.8	NP_569082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXO1	ENST00000366548.8	c.-419G>A		splice_region_variant	2/16	1	NM_130398.4	ENSP00000355506.3
EXO1	ENST00000366548	c.-419G>A		5_prime_UTR_variant	2/16	1	NM_130398.4	ENSP00000355506.3

Frequencies

GnomAD3 genomes AF: 0.618 AC: 93775 AN: 151740 Hom.: 29508 Cov.: 31

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.798

Gnomad SAS AF: 0.547

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.580

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.614

GnomAD4 exome AF: 0.611 AC: 11 AN: 18 Hom.: 3 Cov.: 0 AF XY: 0.625 AC XY: 10 AN XY: 16

Gnomad4 FIN exome AF: 0.750

Gnomad4 NFE exome AF: 0.500

GnomAD4 genome AF: 0.618 AC: 93872 AN: 151858 Hom.: 29551 Cov.: 31 AF XY: 0.622 AC XY: 46153 AN XY: 74186

Gnomad4 AFR AF: 0.706

Gnomad4 AMR AF: 0.680

Gnomad4 ASJ AF: 0.444

Gnomad4 EAS AF: 0.797

Gnomad4 SAS AF: 0.547

Gnomad4 FIN AF: 0.604

Gnomad4 NFE AF: 0.555

Gnomad4 OTH AF: 0.617

Alfa AF: 0.572 Hom.: 36915

Bravo AF: 0.629

Asia WGS AF: 0.678 AC: 2356 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	5.3
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.036
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

Publications

LitVar

Other links and lift over

dbSNP: rs1635517; hg19: chr1-242012033;