rs76350200

Positions:

• chr16-3597786-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.1366+11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0681 in 1,613,988 control chromosomes in the GnomAD database, including 4,100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (603 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3497 hom.)
• Consequence: SLX4 NM_032444.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0620

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 (BayesDel_noAF=-0.92).
• BP6: Variant 16-3597786-A-G is Benign according to our data. Variant chr16-3597786-A-G is described in ClinVar as [Benign]. Clinvar id is 262034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3597786-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLX4	NM_032444.4	c.1366+11T>C		intron_variant		ENST00000294008.4	NP_115820.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4	c.1366+11T>C		intron_variant		5	NM_032444.4	ENSP00000294008	P1
SLX4	ENST00000466154.5	n.2587+11T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0840 AC: 12775 AN: 152062 Hom.: 600 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0833

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.0364

Gnomad SAS AF: 0.0572

Gnomad FIN AF: 0.0869

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0675

Gnomad OTH AF: 0.0766

GnomAD3 exomes AF: 0.0685 AC: 17147 AN: 250472 Hom.: 689 AF XY: 0.0657 AC XY: 8900 AN XY: 135510

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.0782

Gnomad ASJ exome AF: 0.0207

Gnomad EAS exome AF: 0.0350

Gnomad SAS exome AF: 0.0549

Gnomad FIN exome AF: 0.0880

Gnomad NFE exome AF: 0.0674

Gnomad OTH exome AF: 0.0572

GnomAD4 exome AF: 0.0665 AC: 97141 AN: 1461808 Hom.: 3497 Cov.: 33 AF XY: 0.0656 AC XY: 47700 AN XY: 727208

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.0754

Gnomad4 ASJ exome AF: 0.0202

Gnomad4 EAS exome AF: 0.0315

Gnomad4 SAS exome AF: 0.0569

Gnomad4 FIN exome AF: 0.0832

Gnomad4 NFE exome AF: 0.0667

Gnomad4 OTH exome AF: 0.0664

GnomAD4 genome AF: 0.0841 AC: 12795 AN: 152180 Hom.: 603 Cov.: 32 AF XY: 0.0844 AC XY: 6278 AN XY: 74412

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.0830

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.0363

Gnomad4 SAS AF: 0.0578

Gnomad4 FIN AF: 0.0869

Gnomad4 NFE AF: 0.0675

Gnomad4 OTH AF: 0.0758

Alfa AF: 0.0713 Hom.: 69

Bravo AF: 0.0862

Asia WGS AF: 0.0590 AC: 208 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	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	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2019	- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	7.4
DANN	Benign	0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs76350200; hg19: chr16-3647787; COSMIC: COSV53561016; COSMIC: COSV53561016;