chr1-241852289-T-C

Variant names:

• chr1-241852289-T-C
• rs4149863
• NM_130398.4:c.162-3T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_130398.4(EXO1):​c.162-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00475 in 1,601,104 control chromosomes in the GnomAD database, including 332 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.026 (166 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (166 hom.)
• Consequence: EXO1 NM_130398.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001119
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.448
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-241852289-T-C is Benign according to our data. Variant chr1-241852289-T-C is described in ClinVar as Benign. ClinVar VariationId is 767770.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0874 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.162-3T>C		splice_region intron	N/A	NP_569082.2	Q9UQ84-1
	EXO1	NM_006027.4		c.162-3T>C		splice_region intron	N/A	NP_006018.4	Q9UQ84-1
	EXO1	NM_001319224.2		c.162-3T>C		splice_region intron	N/A	NP_001306153.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXO1	ENST00000366548.8	TSL:1 MANE Select	c.162-3T>C		splice_region intron	N/A	ENSP00000355506.3	Q9UQ84-1
	EXO1	ENST00000348581.9	TSL:1	c.162-3T>C		splice_region intron	N/A	ENSP00000311873.5	Q9UQ84-1
	EXO1	ENST00000518483.5	TSL:1	c.162-3T>C		splice_region intron	N/A	ENSP00000430251.1	Q9UQ84-4

Frequencies

GnomAD3 genomes AF: 0.0255 AC: 3883 AN: 152196 Hom.: 165 Cov.: 32

Gnomad AFR AF: 0.0896

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00824

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.0186

GnomAD2 exomes AF: 0.00669 AC: 1674 AN: 250124 AF XY: 0.00474

Gnomad AFR exome AF: 0.0919

Gnomad AMR exome AF: 0.00448

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00256 AC: 3705 AN: 1448790 Hom.: 166 Cov.: 28 AF XY: 0.00213 AC XY: 1537 AN XY: 721696

African (AFR) AF: 0.0909 AC: 3016 AN: 33190

American (AMR) AF: 0.00486 AC: 217 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51652

Middle Eastern (MID) AF: 0.00331 AC: 19 AN: 5736

European-Non Finnish (NFE) AF: 0.0000454 AC: 50 AN: 1101962

Other (OTH) AF: 0.00637 AC: 382 AN: 59956

GnomAD4 genome AF: 0.0256 AC: 3904 AN: 152314 Hom.: 166 Cov.: 32 AF XY: 0.0251 AC XY: 1872 AN XY: 74494

African (AFR) AF: 0.0899 AC: 3734 AN: 41558

American (AMR) AF: 0.00817 AC: 125 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.0184 AC: 39 AN: 2114

Alfa AF: 0.0126 Hom.: 76

Bravo AF: 0.0299

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	EXO1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.2
DANN	Benign	0.59
PhyloP100		0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.024
SpliceAI score (max)		0.15		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: rs4149863; hg19: chr1-242015591;