rs112511042

Positions:

• chr16-3600990-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032444.4(SLX4):​c.1152A>G​(p.Pro384=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0628 in 1,613,138 control chromosomes in the GnomAD database, including 3,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (318 hom., cov: 31)
  • Exomes 𝑓: 0.063 (3089 hom.)
• Consequence: SLX4 NM_032444.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.51

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 16-3600990-T-C is Benign according to our data. Variant chr16-3600990-T-C is described in ClinVar as [Benign]. Clinvar id is 262030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3600990-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.07 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.1152A>G	p.Pro384=	synonymous_variant	5/15	ENST00000294008.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.1152A>G	p.Pro384=	synonymous_variant	5/15	5	NM_032444.4	P1
SLX4	ENST00000466154.5	n.2373A>G		non_coding_transcript_exon_variant	3/7	1
SLX4	ENST00000486524.1	n.2706A>G		non_coding_transcript_exon_variant	4/4	2
SLX4	ENST00000697858.1	n.493A>G		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.0632 AC: 9606 AN: 152032 Hom.: 316 Cov.: 31

Gnomad AFR AF: 0.0577

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0737

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0366

Gnomad SAS AF: 0.0531

Gnomad FIN AF: 0.0863

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0655

Gnomad OTH AF: 0.0584

GnomAD3 exomes AF: 0.0613 AC: 15331 AN: 250078 Hom.: 528 AF XY: 0.0601 AC XY: 8132 AN XY: 135382

Gnomad AFR exome AF: 0.0573

Gnomad AMR exome AF: 0.0713

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.0350

Gnomad SAS exome AF: 0.0520

Gnomad FIN exome AF: 0.0873

Gnomad NFE exome AF: 0.0650

Gnomad OTH exome AF: 0.0517

GnomAD4 exome AF: 0.0628 AC: 91737 AN: 1460988 Hom.: 3089 Cov.: 31 AF XY: 0.0621 AC XY: 45129 AN XY: 726822

Gnomad4 AFR exome AF: 0.0580

Gnomad4 AMR exome AF: 0.0682

Gnomad4 ASJ exome AF: 0.0189

Gnomad4 EAS exome AF: 0.0319

Gnomad4 SAS exome AF: 0.0533

Gnomad4 FIN exome AF: 0.0829

Gnomad4 NFE exome AF: 0.0650

Gnomad4 OTH exome AF: 0.0590

GnomAD4 genome AF: 0.0632 AC: 9616 AN: 152150 Hom.: 318 Cov.: 31 AF XY: 0.0643 AC XY: 4784 AN XY: 74396

Gnomad4 AFR AF: 0.0578

Gnomad4 AMR AF: 0.0735

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.0365

Gnomad4 SAS AF: 0.0539

Gnomad4 FIN AF: 0.0863

Gnomad4 NFE AF: 0.0655

Gnomad4 OTH AF: 0.0578

Alfa AF: 0.0615 Hom.: 145

Bravo AF: 0.0626

Asia WGS AF: 0.0570 AC: 198 AN: 3478

EpiCase AF: 0.0568

EpiControl AF: 0.0584

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	-	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 28, 2016	- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Fanconi anemia complementation group P Benign:1

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. -

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
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.079
DANN	Benign	0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs112511042; hg19: chr16-3650991;