16-3581787-G-A

Position:

• chr16-3581787-G-A

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.*555C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00845 in 165,070 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (0 hom.)
• Consequence: SLX4 NM_032444.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.323

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 (BayesDel_noAF=-1.02).
• BP6: Variant 16-3581787-G-A is Benign according to our data. Variant chr16-3581787-G-A is described in ClinVar as [Benign]. Clinvar id is 319134.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 = 0.00892 (1359/152326) while in subpopulation AFR AF= 0.0244 (1016/41584). AF 95% confidence interval is 0.0232. There are 12 homozygotes in gnomad4. There are 657 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.*555C>T		3_prime_UTR_variant	15/15	ENST00000294008.4
SLX4	XM_011522715.4	c.*555C>T		3_prime_UTR_variant	15/15
SLX4	XM_024450471.2	c.*555C>T		3_prime_UTR_variant	15/15
SLX4	XM_047434801.1	c.*555C>T		3_prime_UTR_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.*555C>T		3_prime_UTR_variant	15/15	5	NM_032444.4	P1
	ENST00000573982.1	n.198+409G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00886 AC: 1348 AN: 152208 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00785

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.00282 AC: 36 AN: 12744 Hom.: 0 Cov.: 0 AF XY: 0.00249 AC XY: 16 AN XY: 6438

Gnomad4 AFR exome AF: 0.0187

Gnomad4 AMR exome AF: 0.00549

Gnomad4 ASJ exome AF: 0.00296

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00246

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00194

Gnomad4 OTH exome AF: 0.00776

GnomAD4 genome AF: 0.00892 AC: 1359 AN: 152326 Hom.: 12 Cov.: 33 AF XY: 0.00882 AC XY: 657 AN XY: 74504

Gnomad4 AFR AF: 0.0244

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00745

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00216

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00635 Hom.: 0

Bravo AF: 0.0101

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia complementation group P Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.36
DANN	Benign	0.64

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: rs146163310; hg19: chr16-3631788;