chr16-3589057-C-T

Variant names:

• chr16-3589057-C-T
• rs78635099
• NM_032444.4:c.4581G>A

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.4581G>A​(p.Pro1527Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00551 in 1,614,134 control chromosomes in the GnomAD database, including 220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (120 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (100 hom.)
• Consequence: SLX4 NM_032444.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.14

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=-0.74).
• BP6: Variant 16-3589057-C-T is Benign according to our data. Variant chr16-3589057-C-T is described in ClinVar as [Benign]. Clinvar id is 262054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3589057-C-T is described in Lovd as [Benign]. Variant chr16-3589057-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4	c.4581G>A	p.Pro1527Pro	synonymous_variant	Exon 12 of 15	ENST00000294008.4	NP_115820.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4	c.4581G>A	p.Pro1527Pro	synonymous_variant	Exon 12 of 15	5	NM_032444.4	ENSP00000294008.3

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3220 AN: 152176 Hom.: 119 Cov.: 32

Gnomad AFR AF: 0.0682

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00222

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.00739 AC: 1855 AN: 251086 Hom.: 50 AF XY: 0.00590 AC XY: 801 AN XY: 135810

Gnomad AFR exome AF: 0.0684

Gnomad AMR exome AF: 0.00677

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00448

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00255

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00388 AC: 5669 AN: 1461840 Hom.: 100 Cov.: 32 AF XY: 0.00379 AC XY: 2755 AN XY: 727226

Gnomad4 AFR exome AF: 0.0663

Gnomad4 AMR exome AF: 0.00724

Gnomad4 ASJ exome AF: 0.00394

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00559

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.00174

Gnomad4 OTH exome AF: 0.00773

GnomAD4 genome AF: 0.0212 AC: 3229 AN: 152294 Hom.: 120 Cov.: 32 AF XY: 0.0203 AC XY: 1511 AN XY: 74476

Gnomad4 AFR AF: 0.0683

Gnomad4 AMR AF: 0.00980

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00222

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0101 Hom.: 16

Bravo AF: 0.0241

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00485

EpiControl AF: 0.00373

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group P Benign:3

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:2

Aug 31, 2012

Leiden Open Variation Database

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 16, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.0
DANN	Benign	0.36

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: rs78635099; hg19: chr16-3639058;