1-241858508-A-G

Variant names:

• chr1-241858508-A-G
• rs147677398
• NM_130398.4:c.546A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_130398.4(EXO1):​c.546A>G​(p.Val182Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,611,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: EXO1 NM_130398.4 splice_region, synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.213
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-241858508-A-G is Benign according to our data. Variant chr1-241858508-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3050624.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.213 with no splicing effect.
• BS2: High AC in GnomAd4 at 107 AD gene.

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.546A>G	p.Val182Val	splice_region synonymous	Exon 8 of 16	NP_569082.2	Q9UQ84-1
	EXO1	NM_006027.4		c.546A>G	p.Val182Val	splice_region synonymous	Exon 6 of 14	NP_006018.4	Q9UQ84-1
	EXO1	NM_001319224.2		c.546A>G	p.Val182Val	splice_region synonymous	Exon 7 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.546A>G	p.Val182Val	splice_region synonymous	Exon 8 of 16	ENSP00000355506.3	Q9UQ84-1
	EXO1	ENST00000348581.9	TSL:1	c.546A>G	p.Val182Val	splice_region synonymous	Exon 6 of 14	ENSP00000311873.5	Q9UQ84-1
	EXO1	ENST00000518483.5	TSL:1	c.546A>G	p.Val182Val	splice_region synonymous	Exon 6 of 14	ENSP00000430251.1	Q9UQ84-4

Frequencies

GnomAD3 genomes AF: 0.000696 AC: 106 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000251 AC: 63 AN: 251290 AF XY: 0.000228

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000117 AC: 170 AN: 1458750 Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 78 AN XY: 725834

African (AFR) AF: 0.00260 AC: 87 AN: 33408

American (AMR) AF: 0.000447 AC: 20 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.0000433 AC: 48 AN: 1109188

Other (OTH) AF: 0.000149 AC: 9 AN: 60288

GnomAD4 genome AF: 0.000702 AC: 107 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000752 AC XY: 56 AN XY: 74498

African (AFR) AF: 0.00233 AC: 97 AN: 41580

American (AMR) AF: 0.000261 AC: 4 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000403 Hom.: 0

Bravo AF: 0.000797

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	EXO1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.2
DANN	Benign	0.63
PhyloP100		0.21
Mutation Taster		=97/3	polymorphism

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: rs147677398; hg19: chr1-242021810;