NM_032444.4:c.3671A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_032444.4(SLX4):​c.3671A>T​(p.Glu1224Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1224Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.228

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: Likely_benign. The variant received -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.013830125).
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000342 (52/152012) while in subpopulation AFR AF = 0.00125 (52/41438). AF 95% confidence interval is 0.000983. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLX4NM_032444.4 linkc.3671A>T p.Glu1224Val missense_variant Exon 12 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.3671A>T p.Glu1224Val missense_variant Exon 12 of 15 5 NM_032444.4 ENSP00000294008.3 Q8IY92-1

Frequencies

GnomAD3 genomes
AF:
0.000342
AC:
52
AN:
151894
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00126
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000798
AC:
20
AN:
250712
AF XY:
0.0000663
show subpopulations
Gnomad AFR exome
AF:
0.00106
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000308
AC:
45
AN:
1461804
Hom.:
0
Cov.:
37
AF XY:
0.0000344
AC XY:
25
AN XY:
727206
show subpopulations
African (AFR)
AF:
0.00102
AC:
34
AN:
33480
American (AMR)
AF:
0.000112
AC:
5
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53332
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1112012
Other (OTH)
AF:
0.0000828
AC:
5
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
4
9
13
18
22
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome 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
GnomAD4 genome
AF:
0.000342
AC:
52
AN:
152012
Hom.:
0
Cov.:
32
AF XY:
0.000363
AC XY:
27
AN XY:
74324
show subpopulations
African (AFR)
AF:
0.00125
AC:
52
AN:
41438
American (AMR)
AF:
0.00
AC:
0
AN:
15264
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5140
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4806
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10596
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67982
Other (OTH)
AF:
0.00
AC:
0
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.489
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:
0.00
Hom.:
0
Bravo
AF:
0.000280
ExAC
AF:
0.0000659
AC:
8

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 02, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: SLX4 c.3671A>T (p.Glu1224Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 250712 control chromosomes. This frequency does not allow for any conclusion about variant significance. To our knowledge, no occurrence of c.3671A>T in individuals affected with Fanconi Anemia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 456312). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Fanconi anemia Uncertain:1
Nov 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1224 of the SLX4 protein (p.Glu1224Val). This variant is present in population databases (rs566584111, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with SLX4-related conditions. ClinVar contains an entry for this variant (Variation ID: 456312). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Fanconi anemia complementation group P Uncertain:1
Apr 23, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:1
Oct 21, 2024
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Reported as a germline variant in a pediatric patient with craniopharyngioma (PMID: 34301788); This variant is associated with the following publications: (PMID: 34301788) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.58
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
6.3
DANN
Benign
0.93
DEOGEN2
Benign
0.073
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.35
T
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.014
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.5
L
PhyloP100
0.23
PrimateAI
Benign
0.23
T
PROVEAN
Benign
-1.7
N
REVEL
Benign
0.020
Sift
Benign
0.11
T
Sift4G
Benign
0.12
T
Polyphen
0.031
B
Vest4
0.21
MVP
0.11
MPC
0.24
ClinPred
0.0086
T
GERP RS
-3.5
Varity_R
0.077
gMVP
0.23
Mutation Taster
=90/10
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: rs566584111; hg19: chr16-3639968; API