NM_032444.4:c.3963G>A

Variant names:

• chr16-3589675-C-T
• rs116781836
• NM_032444.4:c.3963G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_032444.4(SLX4):​c.3963G>A​(p.Pro1321Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00605 in 1,613,938 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (129 hom.)
• Consequence: SLX4 NM_032444.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.936
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group P

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 16-3589675-C-T is Benign according to our data. Variant chr16-3589675-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.936 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00883 (1344/152242) while in subpopulation SAS AF = 0.0448 (216/4820). AF 95% confidence interval is 0.0399. There are 15 homozygotes in GnomAd4. There are 687 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032444.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	NM_032444.4	MANE Select	c.3963G>A	p.Pro1321Pro	synonymous	Exon 12 of 15	NP_115820.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	ENST00000294008.4	TSL:5 MANE Select	c.3963G>A	p.Pro1321Pro	synonymous	Exon 12 of 15	ENSP00000294008.3

Frequencies

GnomAD3 genomes AF: 0.00882 AC: 1342 AN: 152124 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00505

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0456

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00916 AC: 2301 AN: 251260 AF XY: 0.0107

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.00477

Gnomad ASJ exome AF: 0.0135

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.00357

Gnomad OTH exome AF: 0.00863

GnomAD4 exome AF: 0.00576 AC: 8416 AN: 1461696 Hom.: 129 Cov.: 38 AF XY: 0.00694 AC XY: 5044 AN XY: 727134

African (AFR) AF: 0.0182 AC: 609 AN: 33480

American (AMR) AF: 0.00456 AC: 204 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 307 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0439 AC: 3785 AN: 86258

European-Finnish (FIN) AF: 0.000413 AC: 22 AN: 53258

Middle Eastern (MID) AF: 0.0324 AC: 187 AN: 5768

European-Non Finnish (NFE) AF: 0.00255 AC: 2834 AN: 1111992

Other (OTH) AF: 0.00767 AC: 463 AN: 60390

GnomAD4 genome AF: 0.00883 AC: 1344 AN: 152242 Hom.: 15 Cov.: 32 AF XY: 0.00923 AC XY: 687 AN XY: 74436

African (AFR) AF: 0.0180 AC: 749 AN: 41542

American (AMR) AF: 0.00504 AC: 77 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0448 AC: 216 AN: 4820

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00325 AC: 221 AN: 68026

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.00708 Hom.: 5

Bravo AF: 0.00826

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.00600

EpiControl AF: 0.00533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group P Benign:3

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 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

Oct 26, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Fanconi anemia Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:1

Jul 23, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1, BP4, BP7 c.3963G>A, located in exon 12 of the SLX4 gene, is predicted to result in no splicing alteration (according to SpliceAI) and no amino acid change, p.(Pro1321=)(BP4, BP7). The variant allele was found in 1253/30524 alleles (43 homozygous), with a filtering allele frequency of 3.8% at 99% confidence, within the South Asian population in the gnomAD v2.1.1 database (non-cancer data set)(BA1). To our knowledge, functional studies have not been reported for this variant. In addition, the variant was also identified in the ClinVar database (3x likely benign, 5x benign) and in the LOVD database (2x likely benign, 1x benign). Based on currently available information, c.3963G>A is classified as a benign variant according to ACMG guidelines.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.9
DANN	Benign	0.54
PhyloP100		-0.94
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs116781836; hg19: chr16-3639676;