1-241848731-G-A

Variant names:

• chr1-241848731-G-A
• rs1635517
• NM_130398.4:c.-419G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 18 publications found

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]

EXO1 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130398.4. 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
	EXO1	NM_130398.4	MANE Select	c.-419G>A		splice_region	Exon 2 of 16	NP_569082.2	Q9UQ84-1
	EXO1	NM_130398.4	MANE Select	c.-419G>A		5_prime_UTR	Exon 2 of 16	NP_569082.2	Q9UQ84-1
	EXO1	NM_001319224.2		c.-314G>A		splice_region	Exon 2 of 15	NP_001306153.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXO1	ENST00000366548.8	TSL:1 MANE Select	c.-419G>A		splice_region	Exon 2 of 16	ENSP00000355506.3	Q9UQ84-1
	EXO1	ENST00000366548.8	TSL:1 MANE Select	c.-419G>A		5_prime_UTR	Exon 2 of 16	ENSP00000355506.3	Q9UQ84-1
	EXO1	ENST00000348581.9	TSL:1	c.-314G>A		5_prime_UTR	Exon 1 of 14	ENSP00000311873.5	Q9UQ84-1

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

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.750 AC: 6 AN: 8

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 5 AN: 10

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000199620), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.706 AC: 29235 AN: 41402

American (AMR) AF: 0.680 AC: 10370 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1540 AN: 3470

East Asian (EAS) AF: 0.797 AC: 4103 AN: 5146

South Asian (SAS) AF: 0.547 AC: 2627 AN: 4802

European-Finnish (FIN) AF: 0.604 AC: 6359 AN: 10530

Middle Eastern (MID) AF: 0.592 AC: 173 AN: 292

European-Non Finnish (NFE) AF: 0.555 AC: 37695 AN: 67956

Other (OTH) AF: 0.617 AC: 1298 AN: 2104

Alfa AF: 0.576 Hom.: 86296

Bravo AF: 0.629

Asia WGS AF: 0.678 AC: 2356 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	5.3
DANN	Benign	0.85
PhyloP100		-0.091
PromoterAI		-0.15	Neutral
Mutation Taster		=297/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1635517; hg19: chr1-242012033;