rs79842542

chr16-3606624-G-Achr16-3606624-G-Cchr16-3606624-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032444.4(SLX4):c.610C>T(p.Arg204Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0637 in 1,614,118 control chromosomes in the GnomAD database, including 3,519 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R204G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.068 (366 hom., cov: 32)
  • Exomes 𝑓: 0.063 (3153 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.07

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026601255).
• BP6: Variant 16-3606624-G-A is Benign according to our data. Variant chr16-3606624-G-A is described in ClinVar as [Benign]. Clinvar id is 262056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3606624-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.610C>T	p.Arg204Cys	missense_variant	3/15	ENST00000294008.4
SLX4	XM_024450471.2	c.610C>T	p.Arg204Cys	missense_variant	3/15
SLX4	XM_011522715.4	c.610C>T	p.Arg204Cys	missense_variant	3/15
SLX4	XR_007064923.1	n.1259C>T		non_coding_transcript_exon_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.610C>T	p.Arg204Cys	missense_variant	3/15	5	NM_032444.4	P1
SLX4	ENST00000466154.5	n.905C>T		non_coding_transcript_exon_variant	2/7	1
SLX4	ENST00000486524.1	n.1238C>T		non_coding_transcript_exon_variant	3/4	2
SLX4	ENST00000697858.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0675 AC: 10274 AN: 152126 Hom.: 366 Cov.: 32

Gnomad AFR AF: 0.0725

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0757

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.0363

Gnomad SAS AF: 0.0532

Gnomad FIN AF: 0.0867

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0656

Gnomad OTH AF: 0.0622

GnomAD3 exomes AF: 0.0630 AC: 15838 AN: 251474 Hom.: 582 AF XY: 0.0614 AC XY: 8349 AN XY: 135914

Gnomad AFR exome AF: 0.0738

Gnomad AMR exome AF: 0.0733

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.0352

Gnomad SAS exome AF: 0.0522

Gnomad FIN exome AF: 0.0882

Gnomad NFE exome AF: 0.0654

Gnomad OTH exome AF: 0.0521

GnomAD4 exome AF: 0.0633 AC: 92592 AN: 1461874 Hom.: 3153 Cov.: 33 AF XY: 0.0626 AC XY: 45515 AN XY: 727236

Gnomad4 AFR exome AF: 0.0724

Gnomad4 AMR exome AF: 0.0699

Gnomad4 ASJ exome AF: 0.0189

Gnomad4 EAS exome AF: 0.0318

Gnomad4 SAS exome AF: 0.0534

Gnomad4 FIN exome AF: 0.0831

Gnomad4 NFE exome AF: 0.0652

Gnomad4 OTH exome AF: 0.0598

GnomAD4 genome AF: 0.0675 AC: 10277 AN: 152244 Hom.: 366 Cov.: 32 AF XY: 0.0685 AC XY: 5097 AN XY: 74446

Gnomad4 AFR AF: 0.0725

Gnomad4 AMR AF: 0.0754

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.0362

Gnomad4 SAS AF: 0.0541

Gnomad4 FIN AF: 0.0867

Gnomad4 NFE AF: 0.0656

Gnomad4 OTH AF: 0.0616

Alfa AF: 0.0576 Hom.: 427

Bravo AF: 0.0676

TwinsUK AF: 0.0612 AC: 227

ALSPAC AF: 0.0623 AC: 240

ESP6500AA AF: 0.0781 AC: 343

ESP6500EA AF: 0.0678 AC: 583

ExAC AF: 0.0642 AC: 7790

Asia WGS AF: 0.0540 AC: 190 AN: 3478

EpiCase AF: 0.0568

EpiControl AF: 0.0586

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2016	- -
Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 31, 2012	Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker. -

Fanconi anemia complementation group P Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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. -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.48
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.19
MPC		0.091
ClinPred		0.026	T
GERP RS		3.1
Varity_R		0.37
gMVP		0.34

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: rs79842542; hg19: chr16-3656625; COSMIC: COSV53561032;