rs79448721

Positions:

• chr16-3590892-C-A
• chr16-3590892-C-G
• chr16-3590892-C-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.2746G>T​(p.Ala916Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,614,054 control chromosomes in the GnomAD database, including 37 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A916V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0089 (26 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (11 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.110

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=0.002067536).
• BP6: Variant 16-3590892-C-A is Benign according to our data. Variant chr16-3590892-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 241674.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 = 0.00894 (1361/152168) while in subpopulation AFR AF= 0.0312 (1296/41506). AF 95% confidence interval is 0.0298. There are 26 homozygotes in gnomad4. There are 665 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.2746G>T	p.Ala916Ser	missense_variant	12/15	ENST00000294008.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.2746G>T	p.Ala916Ser	missense_variant	12/15	5	NM_032444.4	P1

Frequencies

GnomAD3 genomes AF: 0.00894 AC: 1360 AN: 152050 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

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: 0.0000735

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00233 AC: 586 AN: 251472 Hom.: 8 AF XY: 0.00172 AC XY: 234 AN XY: 135916

Gnomad AFR exome AF: 0.0316

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000943 AC: 1378 AN: 1461886 Hom.: 11 Cov.: 36 AF XY: 0.000793 AC XY: 577 AN XY: 727242

Gnomad4 AFR exome AF: 0.0336

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00894 AC: 1361 AN: 152168 Hom.: 26 Cov.: 32 AF XY: 0.00894 AC XY: 665 AN XY: 74386

Gnomad4 AFR AF: 0.0312

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00220 Hom.: 47

Bravo AF: 0.0107

ESP6500AA AF: 0.0332 AC: 146

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00282 AC: 342

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group P Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 08, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.68
DANN	Benign	0.52
DEOGEN2	Benign	0.024	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.035
Sift	Benign	0.48	T
Sift4G	Benign	0.76	T
Polyphen		0.010	B
Vest4		0.095
MVP		0.067
MPC		0.055
ClinPred		0.0020	T
GERP RS		-4.9
Varity_R		0.030
gMVP		0.15

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: rs79448721; hg19: chr16-3640893;