rs77306735

chr16-3608543-C-Achr16-3608543-C-G

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.422G>T(p.Gly141Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,614,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G141W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.0990

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=0.004153013).
• BP6: Variant 16-3608543-C-A is Benign according to our data. Variant chr16-3608543-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 423992.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00129 (197/152248) while in subpopulation AFR AF= 0.00443 (184/41548). AF 95% confidence interval is 0.00391. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.422G>T	p.Gly141Val	missense_variant	2/15	ENST00000294008.4
SLX4	XM_024450471.2	c.422G>T	p.Gly141Val	missense_variant	2/15
SLX4	XM_011522715.4	c.422G>T	p.Gly141Val	missense_variant	2/15
SLX4	XR_007064923.1	n.1071G>T		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.422G>T	p.Gly141Val	missense_variant	2/15	5	NM_032444.4	P1
SLX4	ENST00000466154.5	n.717G>T		non_coding_transcript_exon_variant	1/7	1
SLX4	ENST00000486524.1	n.1050G>T		non_coding_transcript_exon_variant	2/4	2
SLX4	ENST00000697859.1	n.1044G>T		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00442

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000310 AC: 78 AN: 251488 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135918

Gnomad AFR exome AF: 0.00394

Gnomad AMR exome AF: 0.000231

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: 0.0000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000176 AC: 257 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.000154 AC XY: 112 AN XY: 727244

Gnomad4 AFR exome AF: 0.00627

Gnomad4 AMR exome AF: 0.000224

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: 0.0000171

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74448

Gnomad4 AFR AF: 0.00443

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.0000562 Hom.: 0

Bravo AF: 0.00156

ESP6500AA AF: 0.00228 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000346 AC: 42

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	SLX4: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2018	The G141V variant in the SLX4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G141V variant is observed in 105/24034 (0.44%) alleles from individuals of African background, in large population cohorts (Lek et al., 2016). The G141V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret G141V as a variant of uncertain significance. -

Fanconi anemia Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 25, 2015

- -

Fanconi anemia complementation group P Benign:1

Likely benign, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

SLX4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 10, 2022

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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	4.6
Dann	Benign	0.81
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.028
Sift	Benign	0.14	T
Sift4G	Uncertain	0.036	D
Polyphen		0.023	B
Vest4		0.24
MVP		0.088
MPC		0.21
ClinPred		0.014	T
GERP RS		0.014
Varity_R		0.094
gMVP		0.18

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: rs77306735; hg19: chr16-3658544;