rs77021998

chr16-3584860-G-Achr16-3584860-G-C

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.4648C>T(p.Arg1550Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 1,612,578 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1550Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (15 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.27

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=0.014596283).
• BP6: Variant 16-3584860-G-A is Benign according to our data. Variant chr16-3584860-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 215538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3584860-G-A is described in Lovd as [Likely_benign]. Variant chr16-3584860-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00208 (317/152314) while in subpopulation NFE AF= 0.00354 (241/68030). AF 95% confidence interval is 0.00318. There are 0 homozygotes in gnomad4. There are 122 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.4648C>T	p.Arg1550Trp	missense_variant	13/15	ENST00000294008.4
SLX4	XM_024450471.2	c.4648C>T	p.Arg1550Trp	missense_variant	13/15
SLX4	XM_011522715.4	c.4645C>T	p.Arg1549Trp	missense_variant	13/15
SLX4	XM_047434801.1	c.3646C>T	p.Arg1216Trp	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.4648C>T	p.Arg1550Trp	missense_variant	13/15	5	NM_032444.4	P1

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 317 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00275 AC: 692 AN: 251484 Hom.: 4 AF XY: 0.00270 AC XY: 367 AN XY: 135918

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00550

Gnomad NFE exome AF: 0.00446

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00294 AC: 4300 AN: 1460264 Hom.: 15 Cov.: 30 AF XY: 0.00286 AC XY: 2081 AN XY: 726520

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00459

Gnomad4 NFE exome AF: 0.00339

Gnomad4 OTH exome AF: 0.00308

GnomAD4 genome AF: 0.00208 AC: 317 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74478

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.00354

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00297 Hom.: 2

Bravo AF: 0.00172

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00327 AC: 397

EpiCase AF: 0.00262

EpiControl AF: 0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	SLX4: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 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, 23211700, 27153395, 22383991, 22911665) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:3

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	Eurofins Ntd Llc (ga)	May 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 27, 2016	- -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 21, 2020	- -

Fanconi anemia complementation group A Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Fanconi anemia complementation group P Benign:1

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	0.092
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	14
Dann	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.018
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.070	T
Polyphen		0.060	B
Vest4		0.74
MVP		0.12
MPC		0.060
ClinPred		0.017	T
GERP RS		2.4
Varity_R		0.085
gMVP		0.20

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: rs77021998; hg19: chr16-3634861;