rs137976282

chr16-3608544-C-Achr16-3608544-C-Gchr16-3608544-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Moderate BP6 BS1

The NM_032444.4(SLX4):c.421G>T(p.Gly141Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00081 in 1,614,190 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. G141V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (1 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:3
• Conservation: PhyloP100: 0.878

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 -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21543238).
• BP6: Variant 16-3608544-C-A is Benign according to our data. Variant chr16-3608544-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241689.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=8}. Variant chr16-3608544-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000689 (105/152298) while in subpopulation NFE AF= 0.00104 (71/68034). AF 95% confidence interval is 0.000848. There are 0 homozygotes in gnomad4. There are 54 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.421G>T	p.Gly141Trp	missense_variant	2/15	ENST00000294008.4
SLX4	XM_024450471.2	c.421G>T	p.Gly141Trp	missense_variant	2/15
SLX4	XM_011522715.4	c.421G>T	p.Gly141Trp	missense_variant	2/15
SLX4	XR_007064923.1	n.1070G>T		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.421G>T	p.Gly141Trp	missense_variant	2/15	5	NM_032444.4	P1
SLX4	ENST00000466154.5	n.716G>T		non_coding_transcript_exon_variant	1/7	1
SLX4	ENST00000486524.1	n.1049G>T		non_coding_transcript_exon_variant	2/4	2
SLX4	ENST00000697859.1	n.1043G>T		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 105 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000819 AC: 206 AN: 251488 Hom.: 0 AF XY: 0.000912 AC XY: 124 AN XY: 135922

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000822 AC: 1202 AN: 1461892 Hom.: 1 Cov.: 31 AF XY: 0.000829 AC XY: 603 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.000928

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.000689 AC: 105 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.000725 AC XY: 54 AN XY: 74480

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000780 Hom.: 0

Bravo AF: 0.000604

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000824 AC: 100

EpiCase AF: 0.000927

EpiControl AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi anemia complementation group P Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 17, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. The c.421G>T (p.G141W) variant has been previously reported in patients with breast cancer [PMID 23211700, 23840564] -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	SLX4: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2023	Observed in individuals with a personal or family history of breast and other cancers (Shah et al., 2013; de Garibay et al., 2013; Bakker et al., 2013; Fernandez-Rodriguez et al., 2012; Jalkh et al., 2017); Identified in the compound heterozygous state in two siblings with pre-B acute lymphoblastic leukemia; however, these individuals also harbored variants in other genes that may be related to their condition (Spinella et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23840564, 23211700, 22911665, 22401137, 28202063, 26201965, 30995915, 33558524, 28717660, 22383991, 29970176) -

not specified Uncertain:1 Benign:1

Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 31, 2012	Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 05, 2018	- -

Fanconi anemia Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 25, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Fanconi anemia complementation group A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

research

Center of Medical Genetics and Primary Health Care

Apr 08, 2020

ACMG Guidelines 2015 criteria BS1 Benign Strong: GnomAD exomes allele frequency = 0.000819 > 0.000165 derived from the 555 clinically reported variants in gene SLX4 of which 19 pathogenic, 288 uncertain significance and 248 benign. BP1 Benign Supporting: 92 out of 92 non-VUS missense variants in gene SLX4 are benign = 100.0% > threshold of 51.0%, and 248 out of 555 clinically reported variants in gene SLX4 are benign = 44.7% > threshold of 24.0%. BP4 Benign Supporting: 9 benign predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, MVP, MutationAssessor, MutationTaster, PrimateAI and REVEL vs 4 pathogenic predictions from M-CAP, SIFT, PolyPhen-2, Align-GVGD and the position is not conserved. BP6 Benign Supporting: UniProt classifies this variant as polymorphism. This variant has been reported in individuals affected with breast cancer, childhood acute lymphoblastic leukemia, and unspecified cancer types (PMID: 23211700, 23840564, 28202063, 22401137, 26201965, 28717660). Therefore, this variant was classified as a Variant of Unknown Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.073
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.96	D
Vest4		0.80
MVP		0.30
MPC		0.36
ClinPred		0.031	T
GERP RS		2.5
Varity_R		0.099
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: rs137976282; hg19: chr16-3658545;