rs149126845

chr16-3597690-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_032444.4(SLX4):c.1372A>G(p.Lys458Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00078 in 1,613,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K458R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (0 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:4
• Conservation: PhyloP100: 3.22

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0060458183).
• BP6: Variant 16-3597690-T-C is Benign according to our data. Variant chr16-3597690-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407935.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2, Benign=1}. Variant chr16-3597690-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000827 (126/152304) while in subpopulation AMR AF= 0.00131 (20/15300). AF 95% confidence interval is 0.000875. There are 0 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.1372A>G	p.Lys458Glu	missense_variant	7/15	ENST00000294008.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.1372A>G	p.Lys458Glu	missense_variant	7/15	5	NM_032444.4	P1
SLX4	ENST00000466154.5	n.2593A>G		non_coding_transcript_exon_variant	5/7	1

Frequencies

GnomAD3 genomes AF: 0.000828 AC: 126 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000798 AC: 199 AN: 249516 Hom.: 0 AF XY: 0.000879 AC XY: 119 AN XY: 135436

Gnomad AFR exome AF: 0.000191

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.000775 AC: 1133 AN: 1461608 Hom.: 0 Cov.: 32 AF XY: 0.000789 AC XY: 574 AN XY: 727120

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000870

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000827 AC: 126 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000806 AC XY: 60 AN XY: 74470

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00216 Hom.: 0

Bravo AF: 0.00114

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000585 AC: 71

EpiCase AF: 0.00104

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi anemia complementation group P Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 19, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2022	Observed in an individual with seizures and developmental delay who was de novo for a variant in the SLC1A2 gene as well as compound heterozygous for the K458E variant and another SLX4 missense variant; however follow up testing for Fanconi anemia was normal (Guella et al., 2017); Identified in individuals with breast, ovarian, or head/neck cancers, but also observed in controls (Shah et al., 2013; Bakker et al. 2013; Chandrasekharappa et al., 2017; Rizzolo et al., 2019; Song et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23840564, 32546565, 28678401, 22911665, 30613976, 28777935) -

not specified Uncertain:1 Benign:1

Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 31, 2012	Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 13, 2020	DNA sequence analysis of the SLX4 gene demonstrated a sequence change, c.1372A>G, in exon 7 that results in an amino acid change, p.Lys458Glu. This sequence change has been previously described in a patient with breast cancer, however there is not enough evidence to support the pathogenicity of this sequence change in these studies (PMID: 22911665 and PMID: 23840564). This sequence change has been described in the gnomAD database with a low population frequency of 0.075% (dbSNP rs149126845). The p.Lys458Glu change affects a highly conserved amino acid residue located in a domain of the SLX4 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Lys458Glu substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Lys458Glu change remains unknown at this time. -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 07, 2021	- -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.92	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.083
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.45
MVP		0.32
MPC		0.41
ClinPred		0.081	T
GERP RS		4.2
Varity_R		0.35
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs149126845; hg19: chr16-3647691;