rs77985244

chr16-3595606-A-G

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.2012T>C(p.Leu671Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0645 in 1,613,608 control chromosomes in the GnomAD database, including 3,591 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (408 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3183 hom.)
• Consequence: SLX4 NM_032444.4 missense, splice_region
• Scores: Splicing: ADA: 0.00002109
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.591

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=0.0028672218).
• BP6: Variant 16-3595606-A-G is Benign according to our data. Variant chr16-3595606-A-G is described in ClinVar as [Benign]. Clinvar id is 262040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3595606-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.2012T>C	p.Leu671Ser	missense_variant, splice_region_variant	9/15	ENST00000294008.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.2012T>C	p.Leu671Ser	missense_variant, splice_region_variant	9/15	5	NM_032444.4	P1
SLX4	ENST00000466154.5			downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0721 AC: 10971 AN: 152082 Hom.: 405 Cov.: 32

Gnomad AFR AF: 0.0891

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0759

Gnomad ASJ AF: 0.0188

Gnomad EAS AF: 0.0365

Gnomad SAS AF: 0.0536

Gnomad FIN AF: 0.0867

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0656

Gnomad OTH AF: 0.0669

GnomAD3 exomes AF: 0.0636 AC: 15922 AN: 250160 Hom.: 589 AF XY: 0.0617 AC XY: 8352 AN XY: 135474

Gnomad AFR exome AF: 0.0894

Gnomad AMR exome AF: 0.0725

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.0349

Gnomad SAS exome AF: 0.0522

Gnomad FIN exome AF: 0.0874

Gnomad NFE exome AF: 0.0650

Gnomad OTH exome AF: 0.0539

GnomAD4 exome AF: 0.0637 AC: 93133 AN: 1461408 Hom.: 3183 Cov.: 32 AF XY: 0.0629 AC XY: 45760 AN XY: 727010

Gnomad4 AFR exome AF: 0.0862

Gnomad4 AMR exome AF: 0.0698

Gnomad4 ASJ exome AF: 0.0189

Gnomad4 EAS exome AF: 0.0315

Gnomad4 SAS exome AF: 0.0535

Gnomad4 FIN exome AF: 0.0827

Gnomad4 NFE exome AF: 0.0652

Gnomad4 OTH exome AF: 0.0612

GnomAD4 genome AF: 0.0722 AC: 10984 AN: 152200 Hom.: 408 Cov.: 32 AF XY: 0.0727 AC XY: 5409 AN XY: 74414

Gnomad4 AFR AF: 0.0892

Gnomad4 AMR AF: 0.0756

Gnomad4 ASJ AF: 0.0188

Gnomad4 EAS AF: 0.0364

Gnomad4 SAS AF: 0.0545

Gnomad4 FIN AF: 0.0867

Gnomad4 NFE AF: 0.0656

Gnomad4 OTH AF: 0.0662

Alfa AF: 0.0629 Hom.: 211

Bravo AF: 0.0731

TwinsUK AF: 0.0599 AC: 222

ALSPAC AF: 0.0620 AC: 239

ESP6500AA AF: 0.0915 AC: 402

ESP6500EA AF: 0.0677 AC: 582

ExAC AF: 0.0654 AC: 7939

Asia WGS AF: 0.0570 AC: 201 AN: 3478

EpiCase AF: 0.0570

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	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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 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 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	0.065
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	8.3
Dann	Benign	0.19
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00081	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.2	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.044
Sift	Benign	0.59	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.076
MPC		0.073
ClinPred		0.00043	T
GERP RS		0.88
Varity_R		0.16
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		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: rs77985244; hg19: chr16-3645607;