rs113490934

Positions:

• chr16-3600986-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032444.4(SLX4):​c.1156A>G​(p.Met386Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0628 in 1,613,030 control chromosomes in the GnomAD database, including 3,410 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (320 hom., cov: 32)
  • Exomes 𝑓: 0.063 (3090 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.353

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031724274).
• BP6: Variant 16-3600986-T-C is Benign according to our data. Variant chr16-3600986-T-C is described in ClinVar as [Benign]. Clinvar id is 262032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3600986-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.1156A>G	p.Met386Val	missense_variant	5/15	ENST00000294008.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.1156A>G	p.Met386Val	missense_variant	5/15	5	NM_032444.4	P1
SLX4	ENST00000466154.5	n.2377A>G		non_coding_transcript_exon_variant	3/7	1
SLX4	ENST00000486524.1	n.2710A>G		non_coding_transcript_exon_variant	4/4	2
SLX4	ENST00000697858.1	n.497A>G		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.0632 AC: 9607 AN: 152030 Hom.: 319 Cov.: 32

Gnomad AFR AF: 0.0577

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0739

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0366

Gnomad SAS AF: 0.0532

Gnomad FIN AF: 0.0863

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0655

Gnomad OTH AF: 0.0580

GnomAD3 exomes AF: 0.0612 AC: 15305 AN: 250000 Hom.: 523 AF XY: 0.0601 AC XY: 8129 AN XY: 135362

Gnomad AFR exome AF: 0.0570

Gnomad AMR exome AF: 0.0713

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.0349

Gnomad SAS exome AF: 0.0520

Gnomad FIN exome AF: 0.0871

Gnomad NFE exome AF: 0.0649

Gnomad OTH exome AF: 0.0517

GnomAD4 exome AF: 0.0628 AC: 91682 AN: 1460882 Hom.: 3090 Cov.: 31 AF XY: 0.0621 AC XY: 45108 AN XY: 726780

Gnomad4 AFR exome AF: 0.0579

Gnomad4 AMR exome AF: 0.0682

Gnomad4 ASJ exome AF: 0.0189

Gnomad4 EAS exome AF: 0.0319

Gnomad4 SAS exome AF: 0.0533

Gnomad4 FIN exome AF: 0.0829

Gnomad4 NFE exome AF: 0.0650

Gnomad4 OTH exome AF: 0.0589

GnomAD4 genome AF: 0.0632 AC: 9616 AN: 152148 Hom.: 320 Cov.: 32 AF XY: 0.0643 AC XY: 4784 AN XY: 74390

Gnomad4 AFR AF: 0.0578

Gnomad4 AMR AF: 0.0736

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.0365

Gnomad4 SAS AF: 0.0541

Gnomad4 FIN AF: 0.0863

Gnomad4 NFE AF: 0.0655

Gnomad4 OTH AF: 0.0574

Alfa AF: 0.0597 Hom.: 405

Bravo AF: 0.0626

TwinsUK AF: 0.0591 AC: 219

ALSPAC AF: 0.0618 AC: 238

ESP6500AA AF: 0.0617 AC: 271

ESP6500EA AF: 0.0669 AC: 575

ExAC AF: 0.0623 AC: 7562

Asia WGS AF: 0.0570 AC: 198 AN: 3478

EpiCase AF: 0.0568

EpiControl AF: 0.0583

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 31, 2012	Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 28, 2016	- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Fanconi anemia complementation group P Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.51
DANN	Benign	0.36
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.4	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.051
Sift	Benign	0.65	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.022
MPC		0.056
ClinPred		0.00079	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.042
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: rs113490934; hg19: chr16-3650987; COSMIC: COSV53565461;