rs58735123

chr16-3590529-A-Gchr16-3590529-A-T

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.3109T>C(p.Leu1037=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,613,078 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (35 hom.)
• Consequence: SLX4 NM_032444.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.930

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 16-3590529-A-G is Benign according to our data. Variant chr16-3590529-A-G is described in ClinVar as [Benign]. Clinvar id is 414702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3590529-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.93 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00188 (286/152262) while in subpopulation EAS AF= 0.0323 (167/5170). AF 95% confidence interval is 0.0283. There are 2 homozygotes in gnomad4. There are 187 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.3109T>C	p.Leu1037=	synonymous_variant	12/15	ENST00000294008.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.3109T>C	p.Leu1037=	synonymous_variant	12/15	5	NM_032444.4	P1

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 287 AN: 152144 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0322

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00621

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00307 AC: 772 AN: 251072 Hom.: 10 AF XY: 0.00289 AC XY: 393 AN XY: 135764

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0322

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.00152 AC: 2225 AN: 1460816 Hom.: 35 Cov.: 37 AF XY: 0.00152 AC XY: 1103 AN XY: 726474

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0383

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.00442

Gnomad4 NFE exome AF: 0.000238

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152262 Hom.: 2 Cov.: 33 AF XY: 0.00251 AC XY: 187 AN XY: 74456

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0323

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00621

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000546 Hom.: 0

Bravo AF: 0.00191

Asia WGS AF: 0.0150 AC: 51 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 specified Benign:1

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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	0.35
Dann	Benign	0.28

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: rs58735123; hg19: chr16-3640530; COSMIC: COSV53568389;