rs781479923

Variant names:

• chr16-3582617-G-GC
• rs781479923
• NM_032444.4:c.5229dupG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_032444.4(SLX4):​c.5229dupG​(p.Gln1744AlafsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLX4 NM_032444.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -2.62

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]

ENSG00000261938 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0501 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-3582617-G-GC is Pathogenic according to our data. Variant chr16-3582617-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 456333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4	c.5229dupG	p.Gln1744AlafsTer34	frameshift_variant	Exon 15 of 15	ENST00000294008.4	NP_115820.2
SLX4	XM_024450471.2	c.5229dupG	p.Gln1744AlafsTer34	frameshift_variant	Exon 15 of 15		XP_024306239.1
SLX4	XM_011522715.4	c.5226dupG	p.Gln1743AlafsTer34	frameshift_variant	Exon 15 of 15		XP_011521017.1
SLX4	XM_047434801.1	c.4227dupG	p.Gln1410AlafsTer34	frameshift_variant	Exon 11 of 11		XP_047290757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4	c.5229dupG	p.Gln1744AlafsTer34	frameshift_variant	Exon 15 of 15	5	NM_032444.4	ENSP00000294008.3
ENSG00000261938	ENST00000573982.1	n.199-518dupC		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250060 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135414

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461190 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726932

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia Pathogenic:1

Jun 13, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. No experimental studies have been performed to test the effects of this variant on SLX4 protein function or stability. However, it is expected to result in the disruption of the last 91 amino acids (Gln1744-Asn1834) of the SLX4 protein. This removes most of the SLX1 interaction domain, which has been shown to be critical for SLX1-SLX4 complexing, and therefore will affect their Holliday junction resolvase and 5'-flap endonuclease activities (PMID: 19596235, 19596236). This variant has been reported in an individual affected with breast cancer (PMID: 24733792). This variant is present in population databases (rs781479923, ExAC 0.002%). This sequence change results in a premature translational stop signal in the SLX4 gene (p.Gln1744Alafs*34). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 91 amino acids of the SLX4 protein. -

not provided Pathogenic:1

Aug 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs781479923; hg19: chr16-3632618;