rs3751839

Positions:

• chr16-3582334-T-C
• chr16-3582334-T-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.*8A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0679 in 1,607,746 control chromosomes in the GnomAD database, including 4,024 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (567 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3457 hom.)
• Consequence: SLX4 NM_032444.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.90

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-3582334-T-C is Benign according to our data. Variant chr16-3582334-T-C is described in ClinVar as [Benign]. Clinvar id is 262029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3582334-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.*8A>G		3_prime_UTR_variant	15/15	ENST00000294008.4
SLX4	XM_011522715.4	c.*8A>G		3_prime_UTR_variant	15/15
SLX4	XM_024450471.2	c.*8A>G		3_prime_UTR_variant	15/15
SLX4	XM_047434801.1	c.*8A>G		3_prime_UTR_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.*8A>G		3_prime_UTR_variant	15/15	5	NM_032444.4	P1
	ENST00000573982.1	n.199-802T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0813 AC: 12362 AN: 152080 Hom.: 564 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.0827

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.0363

Gnomad SAS AF: 0.0606

Gnomad FIN AF: 0.0856

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0676

Gnomad OTH AF: 0.0790

GnomAD3 exomes AF: 0.0681 AC: 16743 AN: 245926 Hom.: 664 AF XY: 0.0657 AC XY: 8787 AN XY: 133772

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.0782

Gnomad ASJ exome AF: 0.0235

Gnomad EAS exome AF: 0.0357

Gnomad SAS exome AF: 0.0584

Gnomad FIN exome AF: 0.0863

Gnomad NFE exome AF: 0.0676

Gnomad OTH exome AF: 0.0573

GnomAD4 exome AF: 0.0665 AC: 96732 AN: 1455548 Hom.: 3457 Cov.: 32 AF XY: 0.0658 AC XY: 47643 AN XY: 724214

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.0748

Gnomad4 ASJ exome AF: 0.0227

Gnomad4 EAS exome AF: 0.0320

Gnomad4 SAS exome AF: 0.0609

Gnomad4 FIN exome AF: 0.0823

Gnomad4 NFE exome AF: 0.0668

Gnomad4 OTH exome AF: 0.0661

GnomAD4 genome AF: 0.0813 AC: 12377 AN: 152198 Hom.: 567 Cov.: 32 AF XY: 0.0810 AC XY: 6029 AN XY: 74414

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.0824

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.0362

Gnomad4 SAS AF: 0.0611

Gnomad4 FIN AF: 0.0856

Gnomad4 NFE AF: 0.0676

Gnomad4 OTH AF: 0.0773

Alfa AF: 0.0677 Hom.: 188

Bravo AF: 0.0827

Asia WGS AF: 0.0590 AC: 206 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

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	-	- -

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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.026
DANN	Benign	0.25

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: rs3751839; hg19: chr16-3632335;