rs139287784

chr16-3590663-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_032444.4(SLX4):c.2975G>A(p.Gly992Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000497 in 1,614,196 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (1 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 0.448

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.006367922).
• BP6: Variant 16-3590663-C-T is Benign according to our data. Variant chr16-3590663-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 319162.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=7, Likely_benign=1}. Variant chr16-3590663-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000538 (82/152360) while in subpopulation AMR AF= 0.00183 (28/15310). AF 95% confidence interval is 0.0013. There are 0 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.2975G>A	p.Gly992Glu	missense_variant	12/15	ENST00000294008.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.2975G>A	p.Gly992Glu	missense_variant	12/15	5	NM_032444.4	P1

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000534 AC: 134 AN: 251152 Hom.: 0 AF XY: 0.000486 AC XY: 66 AN XY: 135738

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000493 AC: 721 AN: 1461836 Hom.: 1 Cov.: 37 AF XY: 0.000501 AC XY: 364 AN XY: 727214

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000342

Gnomad4 OTH exome AF: 0.00132

GnomAD4 genome AF: 0.000538 AC: 82 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.000591 AC XY: 44 AN XY: 74512

Gnomad4 AFR AF: 0.000264

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000611 Hom.: 0

Bravo AF: 0.000608

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000420 AC: 51

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi anemia complementation group P Uncertain:2 Benign:1

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. -
Likely benign, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Aug 18, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	Possible pathogenicity based on finding it once in our laboratory in trans with another variant in an 8-year-old female with limb reduction defects, mild malar hypoplasia, retrognathia, bluish slerae, mild language delay -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 17, 2022	- -

Fanconi anemia Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 29, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 19, 2022

DNA sequence analysis of the SLX4 gene demonstrated a sequence change, c.2975G>A, in exon 12 which results in an amino acid change, p.Gly992Glu. This sequence change does not appear to have been previously described in patients with SLX4-related disorders and has been described in the gnomAD database with a frequency of 0.14% in the Ashkenazi Jewish sub-population (dbSNP rs139287784). The p.Gly992Glu change affects a moderately conserved amino acid residue located in a domain of the SLX4 protein that is not known to be functional. The p.Gly992Glu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to contrasting evidences and the lack of functional studies, the clinical significance of this sequence changes remains unknown at this time. -

SLX4-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2023

The SLX4 c.2975G>A variant is predicted to result in the amino acid substitution p.Gly992Glu. This variant has been reported in several large cohorts of patients with hereditary breast and ovarian cancer (Catucci et al. 2012. PubMed ID: 22383991; De Garibay et al. 2013. PubMed ID: 23211700; Shah et al. 2013. PubMed ID: 23840564; Song et al. 2021. PubMed ID: 32546565) but has also been detected in control populations of ostensibly healthy individuals (Song et al. 2021. PubMed ID: 32546565). Additionally, this variant is reported in 0.14% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-3640664-C-T) and has conflicting interpretations in ClinVar ranging from Uncertain to Benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/319162/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	7.9
Dann	Benign	0.96
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.096
Sift	Benign	0.088	T
Sift4G	Benign	0.13	T
Polyphen		0.81	P
Vest4		0.25
MVP		0.18
MPC		0.27
ClinPred		0.019	T
GERP RS		1.1
Varity_R		0.043
gMVP		0.19

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: rs139287784; hg19: chr16-3640664;