rs28516461

chr16-3606556-G-Achr16-3606556-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032444.4(SLX4):c.678C>T(p.His226=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0356 in 1,614,068 control chromosomes in the GnomAD database, including 3,877 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (1447 hom., cov: 32)
  • Exomes 𝑓: 0.030 (2430 hom.)
• Consequence: SLX4 NM_032444.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.120

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-3606556-G-A is Benign according to our data. Variant chr16-3606556-G-A is described in ClinVar as [Benign]. Clinvar id is 262057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3606556-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.678C>T	p.His226=	synonymous_variant	3/15	ENST00000294008.4
SLX4	XM_024450471.2	c.678C>T	p.His226=	synonymous_variant	3/15
SLX4	XM_011522715.4	c.678C>T	p.His226=	synonymous_variant	3/15
SLX4	XR_007064923.1	n.1327C>T		non_coding_transcript_exon_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.678C>T	p.His226=	synonymous_variant	3/15	5	NM_032444.4	P1
SLX4	ENST00000466154.5	n.973C>T		non_coding_transcript_exon_variant	2/7	1
SLX4	ENST00000486524.1	n.1306C>T		non_coding_transcript_exon_variant	3/4	2
SLX4	ENST00000697858.1	n.19C>T		non_coding_transcript_exon_variant	1/3

Frequencies

GnomAD3 genomes AF: 0.0889 AC: 13520 AN: 152064 Hom.: 1444 Cov.: 32

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.0525

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.0457

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.0843

GnomAD3 exomes AF: 0.0492 AC: 12359 AN: 251426 Hom.: 887 AF XY: 0.0493 AC XY: 6697 AN XY: 135894

Gnomad AFR exome AF: 0.260

Gnomad AMR exome AF: 0.0270

Gnomad ASJ exome AF: 0.0314

Gnomad EAS exome AF: 0.0512

Gnomad SAS exome AF: 0.124

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.0379

GnomAD4 exome AF: 0.0300 AC: 43897 AN: 1461888 Hom.: 2430 Cov.: 33 AF XY: 0.0321 AC XY: 23323 AN XY: 727244

Gnomad4 AFR exome AF: 0.276

Gnomad4 AMR exome AF: 0.0289

Gnomad4 ASJ exome AF: 0.0314

Gnomad4 EAS exome AF: 0.0482

Gnomad4 SAS exome AF: 0.123

Gnomad4 FIN exome AF: 0.0133

Gnomad4 NFE exome AF: 0.0145

Gnomad4 OTH exome AF: 0.0457

GnomAD4 genome AF: 0.0890 AC: 13537 AN: 152180 Hom.: 1447 Cov.: 32 AF XY: 0.0890 AC XY: 6625 AN XY: 74406

Gnomad4 AFR AF: 0.253

Gnomad4 AMR AF: 0.0524

Gnomad4 ASJ AF: 0.0366

Gnomad4 EAS AF: 0.0460

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.0134

Gnomad4 NFE AF: 0.0136

Gnomad4 OTH AF: 0.0834

Alfa AF: 0.0392 Hom.: 238

Bravo AF: 0.0993

Asia WGS AF: 0.105 AC: 363 AN: 3478

EpiCase AF: 0.0181

EpiControl AF: 0.0191

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 04, 2017	- -
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. -

Fanconi anemia complementation group P Benign:2

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

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 25, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.98
Dann	Benign	0.89

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: rs28516461; hg19: chr16-3656557; COSMIC: COSV53564444;