rs149011965

chr16-3589781-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.3857C>T(p.Ala1286Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 1,613,428 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. A1286T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (14 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.412

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=0.002882719).
• BP6: Variant 16-3589781-G-A is Benign according to our data. Variant chr16-3589781-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3589781-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00291 (443/152276) while in subpopulation NFE AF= 0.00366 (249/68024). AF 95% confidence interval is 0.00329. There are 0 homozygotes in gnomad4. There are 240 alleles in male gnomad4 subpopulation. Median coverage is 32. 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.3857C>T	p.Ala1286Val	missense_variant	12/15	ENST00000294008.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.3857C>T	p.Ala1286Val	missense_variant	12/15	5	NM_032444.4	P1

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 443 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00366

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00372 AC: 933 AN: 250582 Hom.: 4 AF XY: 0.00352 AC XY: 477 AN XY: 135532

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0172

Gnomad NFE exome AF: 0.00469

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00321 AC: 4692 AN: 1461152 Hom.: 14 Cov.: 38 AF XY: 0.00303 AC XY: 2206 AN XY: 726904

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0161

Gnomad4 NFE exome AF: 0.00330

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.00291 AC: 443 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.00322 AC XY: 240 AN XY: 74448

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0158

Gnomad4 NFE AF: 0.00366

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00284 Hom.: 1

Bravo AF: 0.00165

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00395 AC: 480

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2020	This variant is associated with the following publications: (PMID: 22911665) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely 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	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	SLX4: BP4, BS1, BS2 -

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. -
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	Aug 11, 2020	- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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	0.11
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.0
Dann	Benign	0.92
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.16	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.0070
Sift	Benign	0.24	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.047
MVP		0.030
MPC		0.076
ClinPred		0.0020	T
GERP RS		-2.3
Varity_R		0.023
gMVP		0.18

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: rs149011965; hg19: chr16-3639782;