rs765960272

Positions:

• chr16-3583190-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_032444.4(SLX4):​c.5060C>G​(p.Pro1687Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,614,240 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000053 (1 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.406

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030932128).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000788 (12/152350) while in subpopulation EAS AF= 0.00135 (7/5180). AF 95% confidence interval is 0.000634. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLX4	NM_032444.4	c.5060C>G	p.Pro1687Arg	missense_variant	14/15	ENST00000294008.4	NP_115820.2
SLX4	XM_024450471.2	c.5060C>G	p.Pro1687Arg	missense_variant	14/15		XP_024306239.1
SLX4	XM_011522715.4	c.5057C>G	p.Pro1686Arg	missense_variant	14/15		XP_011521017.1
SLX4	XM_047434801.1	c.4058C>G	p.Pro1353Arg	missense_variant	10/11		XP_047290757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4	c.5060C>G	p.Pro1687Arg	missense_variant	14/15	5	NM_032444.4	ENSP00000294008	P1
	ENST00000573982.1	n.253G>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 37 AN: 251492 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00147

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1461890 Hom.: 1 Cov.: 33 AF XY: 0.0000701 AC XY: 51 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000882

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74500

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000756

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group P Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 29, 2021	- -

Fanconi anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1687 of the SLX4 protein (p.Pro1687Arg). This variant is present in population databases (rs765960272, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with SLX4-related conditions. ClinVar contains an entry for this variant (Variation ID: 319144). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 20, 2020

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Classified as a variant of uncertain significance in a Korean patient with clinical features indicative of hereditary breast cancer (Park et al., 2018); specific variant information provided by Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 29338689) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.7
DANN	Benign	0.97
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.054
Sift	Benign	0.10	T
Sift4G	Benign	0.39	T
Polyphen		0.95	P
Vest4		0.17
MutPred		0.18		Gain of methylation at P1687 (P = 0.0432);
MVP		0.19
MPC		0.26
ClinPred		0.022	T
GERP RS		1.6
Varity_R		0.033
gMVP		0.15

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: rs765960272; hg19: chr16-3633191;