chr1-241850524-C-T

Variant names:

• chr1-241850524-C-T
• rs4149857
• NM_130398.4:c.99C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_130398.4(EXO1):​c.99C>T​(p.Cys33Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,613,898 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (49 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (44 hom.)
• Consequence: EXO1 NM_130398.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0120
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 1-241850524-C-T is Benign according to our data. Variant chr1-241850524-C-T is described in ClinVar as Benign. ClinVar VariationId is 767769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.012 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2021/152292) while in subpopulation AFR AF = 0.0465 (1934/41560). AF 95% confidence interval is 0.0448. There are 49 homozygotes in GnomAd4. There are 976 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2021 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.99C>T	p.Cys33Cys	synonymous	Exon 4 of 16	NP_569082.2	Q9UQ84-1
	EXO1	NM_006027.4		c.99C>T	p.Cys33Cys	synonymous	Exon 2 of 14	NP_006018.4	Q9UQ84-1
	EXO1	NM_001319224.2		c.99C>T	p.Cys33Cys	synonymous	Exon 3 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.99C>T	p.Cys33Cys	synonymous	Exon 4 of 16	ENSP00000355506.3	Q9UQ84-1
	EXO1	ENST00000348581.9	TSL:1	c.99C>T	p.Cys33Cys	synonymous	Exon 2 of 14	ENSP00000311873.5	Q9UQ84-1
	EXO1	ENST00000518483.5	TSL:1	c.99C>T	p.Cys33Cys	synonymous	Exon 2 of 14	ENSP00000430251.1	Q9UQ84-4

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2016 AN: 152174 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.0465

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

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: 0.0000147

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00324 AC: 815 AN: 251460 AF XY: 0.00230

Gnomad AFR exome AF: 0.0442

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00134 AC: 1957 AN: 1461606 Hom.: 44 Cov.: 31 AF XY: 0.00110 AC XY: 797 AN XY: 727122

African (AFR) AF: 0.0484 AC: 1621 AN: 33474

American (AMR) AF: 0.00235 AC: 105 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111796

Other (OTH) AF: 0.00318 AC: 192 AN: 60384

GnomAD4 genome AF: 0.0133 AC: 2021 AN: 152292 Hom.: 49 Cov.: 32 AF XY: 0.0131 AC XY: 976 AN XY: 74456

African (AFR) AF: 0.0465 AC: 1934 AN: 41560

American (AMR) AF: 0.00418 AC: 64 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00690 Hom.: 17

Bravo AF: 0.0153

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	EXO1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.3
DANN	Benign	0.59
PhyloP100		0.012
Mutation Taster		=98/2	polymorphism

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: rs4149857; hg19: chr1-242013826;