rs4408133

Variant names:

• chr1-241886347-G-C
• rs4408133
• NM_130398.4:c.2405+840G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_130398.4(EXO1):​c.2405+840G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 152,048 control chromosomes in the GnomAD database, including 6,947 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (6947 hom., cov: 33)
• Consequence: EXO1 NM_130398.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.137
• Publications: 4 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=-0.79).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXO1	NM_130398.4	c.2405+840G>C		intron_variant	Intron 15 of 15	ENST00000366548.8	NP_569082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXO1	ENST00000366548.8	c.2405+840G>C		intron_variant	Intron 15 of 15	1	NM_130398.4	ENSP00000355506.3

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44466 AN: 151930 Hom.: 6941 Cov.: 33

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.302

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.293 AC: 44480 AN: 152048 Hom.: 6947 Cov.: 33 AF XY: 0.292 AC XY: 21715 AN XY: 74320

African (AFR) AF: 0.201 AC: 8339 AN: 41478

American (AMR) AF: 0.253 AC: 3867 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1121 AN: 3468

East Asian (EAS) AF: 0.301 AC: 1559 AN: 5180

South Asian (SAS) AF: 0.345 AC: 1664 AN: 4826

European-Finnish (FIN) AF: 0.387 AC: 4071 AN: 10530

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.336 AC: 22872 AN: 67974

Other (OTH) AF: 0.305 AC: 645 AN: 2114

Alfa AF: 0.313 Hom.: 990

Bravo AF: 0.276

Asia WGS AF: 0.307 AC: 1068 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.81
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

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: rs4408133; hg19: chr1-242049649;