rs75182789

chr16-3583104-A-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.5146T>A(p.Ser1716Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00156 in 1,614,234 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (21 hom., cov: 33)
  • Exomes 𝑓: 0.00079 (13 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.97

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00554654).
• BP6: Variant 16-3583104-A-T is Benign according to our data. Variant chr16-3583104-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 241694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00893 (1361/152340) while in subpopulation AFR AF= 0.0313 (1303/41592). AF 95% confidence interval is 0.0299. There are 21 homozygotes in gnomad4. There are 619 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.5146T>A	p.Ser1716Thr	missense_variant	14/15	ENST00000294008.4
SLX4	XM_024450471.2	c.5146T>A	p.Ser1716Thr	missense_variant	14/15
SLX4	XM_011522715.4	c.5143T>A	p.Ser1715Thr	missense_variant	14/15
SLX4	XM_047434801.1	c.4144T>A	p.Ser1382Thr	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.5146T>A	p.Ser1716Thr	missense_variant	14/15	5	NM_032444.4	P1
	ENST00000573982.1	n.199-32A>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00891 AC: 1356 AN: 152222 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00226 AC: 568 AN: 251430 Hom.: 14 AF XY: 0.00146 AC XY: 199 AN XY: 135900

Gnomad AFR exome AF: 0.0316

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000789 AC: 1153 AN: 1461894 Hom.: 13 Cov.: 33 AF XY: 0.000694 AC XY: 505 AN XY: 727248

Gnomad4 AFR exome AF: 0.0276

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00893 AC: 1361 AN: 152340 Hom.: 21 Cov.: 33 AF XY: 0.00831 AC XY: 619 AN XY: 74494

Gnomad4 AFR AF: 0.0313

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00150 Hom.: 1

Bravo AF: 0.0105

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0280 AC: 123

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00294 AC: 357

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group P Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 07, 2020

- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.56
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.56	D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.14
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.43
MVP		0.41
MPC		0.35
ClinPred		0.013	T
GERP RS		5.3
Varity_R		0.20
gMVP		0.30

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: rs75182789; hg19: chr16-3633105; COSMIC: COSV99036719;