rs3810813

chr16-3589826-G-A

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.3812C>T(p.Ser1271Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0597 in 1,613,372 control chromosomes in the GnomAD database, including 3,590 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (280 hom., cov: 32)
  • Exomes 𝑓: 0.061 (3310 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.04

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=0.0015541315).
• BP6: Variant 16-3589826-G-A is Benign according to our data. Variant chr16-3589826-G-A is described in ClinVar as [Benign]. Clinvar id is 262050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3589826-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.3812C>T	p.Ser1271Phe	missense_variant	12/15	ENST00000294008.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.3812C>T	p.Ser1271Phe	missense_variant	12/15	5	NM_032444.4	P1

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7569 AN: 152140 Hom.: 276 Cov.: 32

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0573

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.0684

Gnomad FIN AF: 0.0704

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0586

Gnomad OTH AF: 0.0479

GnomAD3 exomes AF: 0.0662 AC: 16583 AN: 250642 Hom.: 762 AF XY: 0.0659 AC XY: 8930 AN XY: 135574

Gnomad AFR exome AF: 0.00981

Gnomad AMR exome AF: 0.0801

Gnomad ASJ exome AF: 0.0355

Gnomad EAS exome AF: 0.185

Gnomad SAS exome AF: 0.0663

Gnomad FIN exome AF: 0.0659

Gnomad NFE exome AF: 0.0540

Gnomad OTH exome AF: 0.0576

GnomAD4 exome AF: 0.0607 AC: 88747 AN: 1461114 Hom.: 3310 Cov.: 39 AF XY: 0.0611 AC XY: 44390 AN XY: 726896

Gnomad4 AFR exome AF: 0.00860

Gnomad4 AMR exome AF: 0.0761

Gnomad4 ASJ exome AF: 0.0354

Gnomad4 EAS exome AF: 0.198

Gnomad4 SAS exome AF: 0.0653

Gnomad4 FIN exome AF: 0.0647

Gnomad4 NFE exome AF: 0.0569

Gnomad4 OTH exome AF: 0.0618

GnomAD4 genome AF: 0.0498 AC: 7577 AN: 152258 Hom.: 280 Cov.: 32 AF XY: 0.0510 AC XY: 3797 AN XY: 74466

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.0579

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.177

Gnomad4 SAS AF: 0.0680

Gnomad4 FIN AF: 0.0704

Gnomad4 NFE AF: 0.0586

Gnomad4 OTH AF: 0.0498

Alfa AF: 0.0582 Hom.: 669

Bravo AF: 0.0491

TwinsUK AF: 0.0620 AC: 230

ALSPAC AF: 0.0597 AC: 230

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.0545 AC: 469

ExAC AF: 0.0641 AC: 7783

Asia WGS AF: 0.118 AC: 408 AN: 3478

EpiCase AF: 0.0585

EpiControl AF: 0.0551

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	Sep 13, 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	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	0.20
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.66	P
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.16
MPC		0.37
ClinPred		0.013	T
GERP RS		5.1
Varity_R		0.27
gMVP		0.42

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: rs3810813; hg19: chr16-3639827; COSMIC: COSV53562898;