rs115694169

chr16-3600989-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032444.4(SLX4):c.1153C>A(p.Pro385Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,613,620 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P385P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0092 (20 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (20 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.209

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=0.0049327016).
• BP6: Variant 16-3600989-G-T is Benign according to our data. Variant chr16-3600989-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 262031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3600989-G-T is described in Lovd as [Benign]. Variant chr16-3600989-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00918 (1397/152196) while in subpopulation AFR AF= 0.0277 (1151/41504). AF 95% confidence interval is 0.0264. There are 20 homozygotes in gnomad4. There are 645 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.1153C>A	p.Pro385Thr	missense_variant	5/15	ENST00000294008.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.1153C>A	p.Pro385Thr	missense_variant	5/15	5	NM_032444.4	P1
SLX4	ENST00000466154.5	n.2374C>A		non_coding_transcript_exon_variant	3/7	1
SLX4	ENST00000486524.1	n.2707C>A		non_coding_transcript_exon_variant	4/4	2
SLX4	ENST00000697858.1	n.494C>A		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.00915 AC: 1392 AN: 152078 Hom.: 20 Cov.: 31

Gnomad AFR AF: 0.0277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.00911

GnomAD3 exomes AF: 0.00376 AC: 942 AN: 250206 Hom.: 11 AF XY: 0.00318 AC XY: 431 AN XY: 135458

Gnomad AFR exome AF: 0.0280

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00252

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00185

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00236 AC: 3449 AN: 1461424 Hom.: 20 Cov.: 31 AF XY: 0.00231 AC XY: 1678 AN XY: 727024

Gnomad4 AFR exome AF: 0.0291

Gnomad4 AMR exome AF: 0.00454

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00314

Gnomad4 FIN exome AF: 0.000301

Gnomad4 NFE exome AF: 0.00149

Gnomad4 OTH exome AF: 0.00361

GnomAD4 genome AF: 0.00918 AC: 1397 AN: 152196 Hom.: 20 Cov.: 31 AF XY: 0.00867 AC XY: 645 AN XY: 74422

Gnomad4 AFR AF: 0.0277

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00179

Gnomad4 OTH AF: 0.00901

Alfa AF: 0.00560 Hom.: 0

Bravo AF: 0.00987

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.0207 AC: 91

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00432 AC: 524

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00354

EpiControl AF: 0.00279

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -

Fanconi anemia complementation group P Benign:2

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.48
Dann	Benign	0.37
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.044
Sift	Benign	0.45	T
Sift4G	Benign	0.38	T
Polyphen		0.031	B
Vest4		0.054
MVP		0.12
MPC		0.15
ClinPred		0.0020	T
GERP RS		0.013
Varity_R		0.034
gMVP		0.24

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: rs115694169; hg19: chr16-3650990; COSMIC: COSV99036734;