NM_032444.4:c.1707G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_032444.4(SLX4):​c.1707G>A​(p.Pro569Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,596,398 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000098 ( 1 hom. )

Consequence

SLX4
NM_032444.4 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.994

Publications

1 publications found
Variant links:
Genes affected
SLX4 (HGNC:23845): (SLX4 structure-specific endonuclease subunit) This gene encodes a protein that functions as an assembly component of multiple structure-specific endonucleases. These endonuclease complexes are required for repair of specific types of DNA lesions and critical for cellular responses to replication fork failure. Mutations in this gene were found in patients with Fanconi anemia. [provided by RefSeq, Sep 2016]
SLX4 Gene-Disease associations (from GenCC):
  • Fanconi anemia complementation group P
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
  • Fanconi anemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • familial ovarian cancer
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
  • hereditary breast carcinoma
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.73).
BP6
Variant 16-3596370-C-T is Benign according to our data. Variant chr16-3596370-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241666. Variant chr16-3596370-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241666.
BP7
Synonymous conserved (PhyloP=-0.994 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000414 (63/152336) while in subpopulation AFR AF = 0.00127 (53/41588). AF 95% confidence interval is 0.001. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLX4NM_032444.4 linkc.1707G>A p.Pro569Pro synonymous_variant Exon 8 of 15 ENST00000294008.4 NP_115820.2 Q8IY92-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLX4ENST00000294008.4 linkc.1707G>A p.Pro569Pro synonymous_variant Exon 8 of 15 5 NM_032444.4 ENSP00000294008.3 Q8IY92-1
SLX4ENST00000466154.5 linkn.2928G>A non_coding_transcript_exon_variant Exon 6 of 7 1

Frequencies

GnomAD3 genomes
AF:
0.000414
AC:
63
AN:
152218
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00128
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000130
AC:
29
AN:
222746
AF XY:
0.0000901
show subpopulations
Gnomad AFR exome
AF:
0.00121
Gnomad AMR exome
AF:
0.0000309
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000538
Gnomad NFE exome
AF:
0.0000713
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000976
AC:
141
AN:
1444062
Hom.:
1
Cov.:
32
AF XY:
0.0000964
AC XY:
69
AN XY:
716052
show subpopulations
African (AFR)
AF:
0.00114
AC:
38
AN:
33248
American (AMR)
AF:
0.0000697
AC:
3
AN:
43052
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25636
East Asian (EAS)
AF:
0.0000255
AC:
1
AN:
39148
South Asian (SAS)
AF:
0.000106
AC:
9
AN:
84586
European-Finnish (FIN)
AF:
0.000118
AC:
6
AN:
50640
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5662
European-Non Finnish (NFE)
AF:
0.0000626
AC:
69
AN:
1102544
Other (OTH)
AF:
0.000252
AC:
15
AN:
59546
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
8
17
25
34
42
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000414
AC:
63
AN:
152336
Hom.:
0
Cov.:
32
AF XY:
0.000282
AC XY:
21
AN XY:
74498
show subpopulations
African (AFR)
AF:
0.00127
AC:
53
AN:
41588
American (AMR)
AF:
0.000131
AC:
2
AN:
15304
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5176
South Asian (SAS)
AF:
0.000414
AC:
2
AN:
4828
European-Finnish (FIN)
AF:
0.0000941
AC:
1
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:
0.00
AC:
0
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
3
6
10
13
16
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000153
Hom.:
0
Bravo
AF:
0.000495

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Fanconi anemia Benign:2
Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 16, 2021
Sema4, Sema4
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:curation

- -

Fanconi anemia complementation group P Uncertain:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1
Apr 07, 2017
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
Sep 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

SLX4: BP4, BP7 -

SLX4-related disorder Benign:1
Nov 18, 2021
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.73
CADD
Benign
1.7
DANN
Benign
0.69
PhyloP100
-0.99
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=100/0
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

Publications

Other links and lift over

dbSNP: rs141687678; hg19: chr16-3646371; COSMIC: COSV99568534; COSMIC: COSV99568534; API