rs144776083

Positions:

• chr16-3582588-G-A
• chr16-3582588-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_032444.4(SLX4):​c.5259C>T​(p.Asp1753=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,613,624 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: SLX4 NM_032444.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.645

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 16-3582588-G-A is Benign according to our data. Variant chr16-3582588-G-A is described in ClinVar as [Benign]. Clinvar id is 414716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3582588-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.645 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00108 (164/152320) while in subpopulation SAS AF= 0.0155 (75/4824). AF 95% confidence interval is 0.0127. There are 3 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.5259C>T	p.Asp1753=	synonymous_variant	15/15	ENST00000294008.4
SLX4	XM_024450471.2	c.5259C>T	p.Asp1753=	synonymous_variant	15/15
SLX4	XM_011522715.4	c.5256C>T	p.Asp1752=	synonymous_variant	15/15
SLX4	XM_047434801.1	c.4257C>T	p.Asp1419=	synonymous_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.5259C>T	p.Asp1753=	synonymous_variant	15/15	5	NM_032444.4	P1
	ENST00000573982.1	n.199-548G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152202 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00234 AC: 586 AN: 250316 Hom.: 9 AF XY: 0.00305 AC XY: 413 AN XY: 135546

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0171

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00112 AC: 1634 AN: 1461304 Hom.: 23 Cov.: 32 AF XY: 0.00158 AC XY: 1146 AN XY: 726988

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0157

Gnomad4 FIN exome AF: 0.000151

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152320 Hom.: 3 Cov.: 33 AF XY: 0.00141 AC XY: 105 AN XY: 74470

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0155

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.000669

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group P Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 20, 2021	- -
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. -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	2.6
DANN	Benign	0.81

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: rs144776083; hg19: chr16-3632589; COSMIC: COSV99568438;