16-3589138-A-G

Position:

• chr16-3589138-A-G

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.4500T>C​(p.Asn1500=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 1,613,870 control chromosomes in the GnomAD database, including 256,101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (33045 hom., cov: 31)
  • Exomes 𝑓: 0.54 (223056 hom.)
• Consequence: SLX4 NM_032444.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.753

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=-0.89).
• BP6: Variant 16-3589138-A-G is Benign according to our data. Variant chr16-3589138-A-G is described in ClinVar as [Benign]. Clinvar id is 262053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3589138-A-G is described in Lovd as [Benign]. Variant chr16-3589138-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.753 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLX4	NM_032444.4	c.4500T>C	p.Asn1500=	synonymous_variant	12/15	ENST00000294008.4	NP_115820.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4	c.4500T>C	p.Asn1500=	synonymous_variant	12/15	5	NM_032444.4	ENSP00000294008	P1

Frequencies

GnomAD3 genomes AF: 0.638 AC: 96966 AN: 151922 Hom.: 32978 Cov.: 31

Gnomad AFR AF: 0.875

Gnomad AMI AF: 0.542

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.716

Gnomad SAS AF: 0.774

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.512

Gnomad OTH AF: 0.611

GnomAD3 exomes AF: 0.604 AC: 151712 AN: 251234 Hom.: 47857 AF XY: 0.602 AC XY: 81737 AN XY: 135840

Gnomad AFR exome AF: 0.878

Gnomad AMR exome AF: 0.669

Gnomad ASJ exome AF: 0.487

Gnomad EAS exome AF: 0.720

Gnomad SAS exome AF: 0.761

Gnomad FIN exome AF: 0.515

Gnomad NFE exome AF: 0.513

Gnomad OTH exome AF: 0.559

GnomAD4 exome AF: 0.544 AC: 795369 AN: 1461830 Hom.: 223056 Cov.: 83 AF XY: 0.549 AC XY: 399049 AN XY: 727216

Gnomad4 AFR exome AF: 0.892

Gnomad4 AMR exome AF: 0.657

Gnomad4 ASJ exome AF: 0.482

Gnomad4 EAS exome AF: 0.738

Gnomad4 SAS exome AF: 0.758

Gnomad4 FIN exome AF: 0.517

Gnomad4 NFE exome AF: 0.507

Gnomad4 OTH exome AF: 0.560

GnomAD4 genome AF: 0.639 AC: 97099 AN: 152040 Hom.: 33045 Cov.: 31 AF XY: 0.642 AC XY: 47715 AN XY: 74302

Gnomad4 AFR AF: 0.875

Gnomad4 AMR AF: 0.619

Gnomad4 ASJ AF: 0.488

Gnomad4 EAS AF: 0.716

Gnomad4 SAS AF: 0.774

Gnomad4 FIN AF: 0.515

Gnomad4 NFE AF: 0.512

Gnomad4 OTH AF: 0.616

Alfa AF: 0.533 Hom.: 48719

Bravo AF: 0.654

Asia WGS AF: 0.759 AC: 2640 AN: 3478

EpiCase AF: 0.513

EpiControl AF: 0.517

ClinVar

Significance: Benign

Submissions summary: Benign:9

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	Aug 08, 2016	- -
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. -

Fanconi anemia complementation group P Benign:3

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	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.89
CADD	Benign	2.5
DANN	Benign	0.35

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: rs3810812; hg19: chr16-3639139; COSMIC: COSV53564459;