rs143730668

chr16-3591189-C-Gchr16-3591189-C-T

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.2449G>C(p.Glu817Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,614,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E817D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.57

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03939867).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000164 (24/1461820) while in subpopulation EAS AF= 0.000579 (23/39700). AF 95% confidence interval is 0.000396. There are 0 homozygotes in gnomad4_exome. There are 11 alleles in male gnomad4_exome subpopulation. Median coverage is 36. 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	UniProt
SLX4	NM_032444.4	c.2449G>C	p.Glu817Gln	missense_variant	12/15	ENST00000294008.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.2449G>C	p.Glu817Gln	missense_variant	12/15	5	NM_032444.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152240 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: 0.000961

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251440 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00152

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461820 Hom.: 0 Cov.: 36 AF XY: 0.0000151 AC XY: 11 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000579

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74504

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000963

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000252 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 817 of the SLX4 protein (p.Glu817Gln). This variant is present in population databases (rs143730668, gnomAD 0.2%). 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: 407927). 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. -

Fanconi anemia complementation group P Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.79	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.15
Sift	Benign	0.054	T
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.17
MVP		0.53
MPC		0.16
ClinPred		0.15	T
GERP RS		5.6
Varity_R		0.18
gMVP		0.34

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: rs143730668; hg19: chr16-3641190;