rs3827530

chr16-3589976-G-Achr16-3589976-G-C

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.3662C>T(p.Ala1221Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0603 in 1,613,786 control chromosomes in the GnomAD database, including 3,256 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1221L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.050 (241 hom., cov: 32)
  • Exomes 𝑓: 0.061 (3015 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.330

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=0.0017294586).
• BP6: Variant 16-3589976-G-A is Benign according to our data. Variant chr16-3589976-G-A is described in ClinVar as [Benign]. Clinvar id is 262048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3589976-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.3662C>T	p.Ala1221Val	missense_variant	12/15	ENST00000294008.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.3662C>T	p.Ala1221Val	missense_variant	12/15	5	NM_032444.4	P1

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7559 AN: 151906 Hom.: 241 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0689

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0356

Gnomad SAS AF: 0.0521

Gnomad FIN AF: 0.0859

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0651

Gnomad OTH AF: 0.0473

GnomAD3 exomes AF: 0.0583 AC: 14614 AN: 250722 Hom.: 523 AF XY: 0.0579 AC XY: 7855 AN XY: 135686

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.0690

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.0354

Gnomad SAS exome AF: 0.0522

Gnomad FIN exome AF: 0.0883

Gnomad NFE exome AF: 0.0653

Gnomad OTH exome AF: 0.0503

GnomAD4 exome AF: 0.0614 AC: 89737 AN: 1461762 Hom.: 3015 Cov.: 38 AF XY: 0.0609 AC XY: 44295 AN XY: 727194

Gnomad4 AFR exome AF: 0.00920

Gnomad4 AMR exome AF: 0.0651

Gnomad4 ASJ exome AF: 0.0189

Gnomad4 EAS exome AF: 0.0317

Gnomad4 SAS exome AF: 0.0532

Gnomad4 FIN exome AF: 0.0830

Gnomad4 NFE exome AF: 0.0650

Gnomad4 OTH exome AF: 0.0553

GnomAD4 genome AF: 0.0497 AC: 7556 AN: 152024 Hom.: 241 Cov.: 32 AF XY: 0.0512 AC XY: 3805 AN XY: 74314

Gnomad4 AFR AF: 0.0117

Gnomad4 AMR AF: 0.0686

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.0355

Gnomad4 SAS AF: 0.0530

Gnomad4 FIN AF: 0.0859

Gnomad4 NFE AF: 0.0651

Gnomad4 OTH AF: 0.0468

Alfa AF: 0.0564 Hom.: 184

Bravo AF: 0.0464

TwinsUK AF: 0.0612 AC: 227

ALSPAC AF: 0.0612 AC: 236

ESP6500AA AF: 0.0148 AC: 65

ESP6500EA AF: 0.0669 AC: 575

ExAC AF: 0.0583 AC: 7078

Asia WGS AF: 0.0500 AC: 175 AN: 3478

EpiCase AF: 0.0567

EpiControl AF: 0.0583

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

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	0.081
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	3.2
Dann	Benign	0.93
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.0030
Sift	Benign	0.30	T
Sift4G	Benign	0.34	T
Polyphen		0.019	B
Vest4		0.015
MPC		0.056
ClinPred		0.00066	T
GERP RS		-3.8
Varity_R		0.024
gMVP		0.084

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: rs3827530; hg19: chr16-3639977; COSMIC: COSV53566301;