16-3590476-C-T

Position:

• chr16-3590476-C-T

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.3162G>A​(p.Ser1054Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,614,034 control chromosomes in the GnomAD database, including 1,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (185 hom., cov: 33)
  • Exomes 𝑓: 0.023 (1070 hom.)
• Consequence: SLX4 NM_032444.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -5.33

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]

SLX4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 16-3590476-C-T is Benign according to our data. Variant chr16-3590476-C-T is described in ClinVar as [Benign]. Clinvar id is 262046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3590476-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-5.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLX4	NM_032444.4	c.3162G>A	p.Ser1054Ser	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.3162G>A	p.Ser1054Ser	synonymous_variant	12/15	5	NM_032444.4	ENSP00000294008.3

Frequencies

GnomAD3 genomes AF: 0.0364 AC: 5532 AN: 152136 Hom.: 184 Cov.: 33

Gnomad AFR AF: 0.0795

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0448

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0320

GnomAD3 exomes AF: 0.0329 AC: 8257 AN: 251130 Hom.: 353 AF XY: 0.0365 AC XY: 4958 AN XY: 135842

Gnomad AFR exome AF: 0.0786

Gnomad AMR exome AF: 0.0144

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.0497

Gnomad SAS exome AF: 0.118

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.0253

GnomAD4 exome AF: 0.0225 AC: 32940 AN: 1461780 Hom.: 1070 Cov.: 37 AF XY: 0.0251 AC XY: 18262 AN XY: 727164

Gnomad4 AFR exome AF: 0.0890

Gnomad4 AMR exome AF: 0.0151

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.0474

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.0131

Gnomad4 NFE exome AF: 0.0128

Gnomad4 OTH exome AF: 0.0309

GnomAD4 genome AF: 0.0364 AC: 5535 AN: 152254 Hom.: 185 Cov.: 33 AF XY: 0.0375 AC XY: 2788 AN XY: 74434

Gnomad4 AFR AF: 0.0795

Gnomad4 AMR AF: 0.0235

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.0451

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.0132

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0214 Hom.: 33

Bravo AF: 0.0381

EpiCase AF: 0.0152

EpiControl AF: 0.0148

ClinVar

Significance: Benign

Submissions summary: Benign:8

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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 04, 2017	- -
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 12, 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 28, 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	-0.73
CADD	Benign	0.54
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: rs76488917; hg19: chr16-3640477;