rs111738042

Positions:

• chr16-3582346-T-C
• chr16-3582346-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_032444.4(SLX4):​c.5501A>G​(p.Asn1834Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00755 in 1,611,090 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0056 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0077 (43 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.295

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050572455).
• BP6: Variant 16-3582346-T-C is Benign according to our data. Variant chr16-3582346-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241697.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=7, Uncertain_significance=1}. Variant chr16-3582346-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00564 (859/152336) while in subpopulation NFE AF= 0.0081 (551/68026). AF 95% confidence interval is 0.00754. There are 2 homozygotes in gnomad4. There are 407 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.5501A>G	p.Asn1834Ser	missense_variant	15/15	ENST00000294008.4
SLX4	XM_024450471.2	c.5501A>G	p.Asn1834Ser	missense_variant	15/15
SLX4	XM_011522715.4	c.5498A>G	p.Asn1833Ser	missense_variant	15/15
SLX4	XM_047434801.1	c.4499A>G	p.Asn1500Ser	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.5501A>G	p.Asn1834Ser	missense_variant	15/15	5	NM_032444.4	P1
	ENST00000573982.1	n.199-790T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00564 AC: 859 AN: 152220 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00641

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00988

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00810

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00558 AC: 1388 AN: 248708 Hom.: 6 AF XY: 0.00566 AC XY: 764 AN XY: 134906

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.00467

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00969

Gnomad NFE exome AF: 0.00835

Gnomad OTH exome AF: 0.00622

GnomAD4 exome AF: 0.00775 AC: 11302 AN: 1458754 Hom.: 43 Cov.: 32 AF XY: 0.00754 AC XY: 5475 AN XY: 725810

Gnomad4 AFR exome AF: 0.00126

Gnomad4 AMR exome AF: 0.00394

Gnomad4 ASJ exome AF: 0.00436

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000557

Gnomad4 FIN exome AF: 0.00884

Gnomad4 NFE exome AF: 0.00903

Gnomad4 OTH exome AF: 0.00656

GnomAD4 genome AF: 0.00564 AC: 859 AN: 152336 Hom.: 2 Cov.: 33 AF XY: 0.00546 AC XY: 407 AN XY: 74492

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.00640

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00988

Gnomad4 NFE AF: 0.00810

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00743 Hom.: 4

Bravo AF: 0.00547

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00826 AC: 71

ExAC AF: 0.00544 AC: 660

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00840

EpiControl AF: 0.00865

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	SLX4: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 21, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2021	This variant is associated with the following publications: (PMID: 28051113, 28717660, 22401137, 28202063, 21805310) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 14, 2016	- -
Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 31, 2012	Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Apr 19, 2017	BS1,BP4,BP6; This alteration has an allele frequency that is greater than expected for the associated disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 02, 2021	- -

Fanconi anemia complementation group P Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.2
DANN	Benign	0.82
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.019
Sift	Benign	0.053	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0050	B
Vest4		0.089
MVP		0.12
MPC		0.048
ClinPred		0.0011	T
GERP RS		0.75
Varity_R		0.017
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs111738042; hg19: chr16-3632347; COSMIC: COSV99568934; COSMIC: COSV99568934;