rs118089506

chr16-3608875-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_032444.4(SLX4):c.90C>T(p.Ser30=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00833 in 1,614,138 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (66 hom.)
• Consequence: SLX4 NM_032444.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.52

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=-0.85).
• BP6: Variant 16-3608875-G-A is Benign according to our data. Variant chr16-3608875-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3608875-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00619 (943/152252) while in subpopulation AMR AF= 0.0098 (150/15300). AF 95% confidence interval is 0.00885. There are 4 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.90C>T	p.Ser30=	synonymous_variant	2/15	ENST00000294008.4
SLX4	XM_024450471.2	c.90C>T	p.Ser30=	synonymous_variant	2/15
SLX4	XM_011522715.4	c.90C>T	p.Ser30=	synonymous_variant	2/15
SLX4	XR_007064923.1	n.739C>T		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.90C>T	p.Ser30=	synonymous_variant	2/15	5	NM_032444.4	P1
SLX4	ENST00000466154.5	n.385C>T		non_coding_transcript_exon_variant	1/7	1
SLX4	ENST00000486524.1	n.718C>T		non_coding_transcript_exon_variant	2/4	2
SLX4	ENST00000697859.1	n.712C>T		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.00621 AC: 945 AN: 152134 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00788

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00945

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00604 AC: 1520 AN: 251472 Hom.: 6 AF XY: 0.00661 AC XY: 898 AN XY: 135920

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00523

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00670

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00898

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00855 AC: 12495 AN: 1461886 Hom.: 66 Cov.: 31 AF XY: 0.00871 AC XY: 6335 AN XY: 727244

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00579

Gnomad4 ASJ exome AF: 0.00409

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00718

Gnomad4 FIN exome AF: 0.000618

Gnomad4 NFE exome AF: 0.00981

Gnomad4 OTH exome AF: 0.00803

GnomAD4 genome AF: 0.00619 AC: 943 AN: 152252 Hom.: 4 Cov.: 32 AF XY: 0.00600 AC XY: 447 AN XY: 74452

Gnomad4 AFR AF: 0.00157

Gnomad4 AMR AF: 0.00980

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00747

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00945

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00755 Hom.: 4

Bravo AF: 0.00641

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0110

EpiControl AF: 0.0120

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 06, 2017	- -

Fanconi anemia complementation group P Benign:3

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	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 26, 2021	- -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 28, 2020	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2021	This variant is associated with the following publications: (PMID: 22383991) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SLX4: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	6.8
Dann	Benign	0.55

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: rs118089506; hg19: chr16-3658876;