rs139254595

Positions:

• chr16-3589108-C-A
• chr16-3589108-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_032444.4(SLX4):​c.4530G>T​(p.Leu1510=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: SLX4 NM_032444.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.0320

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 16-3589108-C-A is Benign according to our data. Variant chr16-3589108-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436777.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr16-3589108-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.032 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLX4	NM_032444.4	c.4530G>T	p.Leu1510=	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.4530G>T	p.Leu1510=	synonymous_variant	12/15	5	NM_032444.4	ENSP00000294008	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251104 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135814

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000233 AC: 341 AN: 1461812 Hom.: 0 Cov.: 32 AF XY: 0.000221 AC XY: 161 AN XY: 727210

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000286

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74354

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.000181

EpiCase AF: 0.000436

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 13, 2016	- -
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:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 14, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Fanconi anemia complementation group P Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

SLX4-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.0
DANN	Benign	0.48

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: rs139254595; hg19: chr16-3639109; COSMIC: COSV99568330;