rs143818824

Positions:

• chr16-3582566-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032444.4(SLX4):​c.5281C>T​(p.Arg1761Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,613,784 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (8 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.04

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00684762).
• BP6: Variant 16-3582566-G-A is Benign according to our data. Variant chr16-3582566-G-A is described in ClinVar as [Benign]. Clinvar id is 212221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3582566-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00712 (1085/152342) while in subpopulation AFR AF= 0.0246 (1021/41576). AF 95% confidence interval is 0.0233. There are 15 homozygotes in gnomad4. There are 513 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.5281C>T	p.Arg1761Cys	missense_variant	15/15	ENST00000294008.4
SLX4	XM_024450471.2	c.5281C>T	p.Arg1761Cys	missense_variant	15/15
SLX4	XM_011522715.4	c.5278C>T	p.Arg1760Cys	missense_variant	15/15
SLX4	XM_047434801.1	c.4279C>T	p.Arg1427Cys	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.5281C>T	p.Arg1761Cys	missense_variant	15/15	5	NM_032444.4	P1
	ENST00000573982.1	n.199-570G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00709 AC: 1079 AN: 152224 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00187 AC: 470 AN: 250714 Hom.: 4 AF XY: 0.00138 AC XY: 187 AN XY: 135692

Gnomad AFR exome AF: 0.0269

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000883

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000763 AC: 1115 AN: 1461442 Hom.: 8 Cov.: 33 AF XY: 0.000689 AC XY: 501 AN XY: 727050

Gnomad4 AFR exome AF: 0.0270

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00712 AC: 1085 AN: 152342 Hom.: 15 Cov.: 33 AF XY: 0.00689 AC XY: 513 AN XY: 74498

Gnomad4 AFR AF: 0.0246

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00138 Hom.: 3

Bravo AF: 0.00823

ESP6500AA AF: 0.0239 AC: 105

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00227 AC: 275

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 06, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2021	This variant is associated with the following publications: (PMID: 28678401) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	SLX4: BP4, BS1, BS2 -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 19, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Fanconi anemia complementation group P Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.071
Sift	Benign	0.12	T
Sift4G	Benign	0.090	T
Polyphen		0.58	P
Vest4		0.11
MVP		0.32
MPC		0.075
ClinPred		0.046	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.29

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: rs143818824; hg19: chr16-3632567; COSMIC: COSV53561921;