rs112226642

Variant names:

• chr16-3595582-C-T
• rs112226642
• NM_032444.4:c.2013+23G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032444.4(SLX4):​c.2013+23G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0629 in 1,612,140 control chromosomes in the GnomAD database, including 3,408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (320 hom., cov: 32)
  • Exomes 𝑓: 0.063 (3088 hom.)
• Consequence: SLX4 NM_032444.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.88
• Publications: 11 publications found

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]

SLX4 Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group P

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 16-3595582-C-T is Benign according to our data. Variant chr16-3595582-C-T is described in ClinVar as Benign. ClinVar VariationId is 262041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4	c.2013+23G>A		intron_variant	Intron 9 of 14	ENST00000294008.4	NP_115820.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4	c.2013+23G>A		intron_variant	Intron 9 of 14	5	NM_032444.4	ENSP00000294008.3
SLX4	ENST00000466154.5	n.*29G>A		downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0631 AC: 9597 AN: 152140 Hom.: 319 Cov.: 32

Gnomad AFR AF: 0.0574

Gnomad AMI AF: 0.0901

Gnomad AMR AF: 0.0737

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0364

Gnomad SAS AF: 0.0533

Gnomad FIN AF: 0.0867

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0655

Gnomad OTH AF: 0.0579

GnomAD2 exomes AF: 0.0610 AC: 15149 AN: 248364 AF XY: 0.0597

Gnomad AFR exome AF: 0.0570

Gnomad AMR exome AF: 0.0713

Gnomad ASJ exome AF: 0.0190

Gnomad EAS exome AF: 0.0347

Gnomad FIN exome AF: 0.0873

Gnomad NFE exome AF: 0.0645

Gnomad OTH exome AF: 0.0527

GnomAD4 exome AF: 0.0628 AC: 91725 AN: 1459882 Hom.: 3088 Cov.: 32 AF XY: 0.0621 AC XY: 45121 AN XY: 726298

African (AFR) AF: 0.0577 AC: 1929 AN: 33452

American (AMR) AF: 0.0684 AC: 3057 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 493 AN: 26128

East Asian (EAS) AF: 0.0315 AC: 1250 AN: 39694

South Asian (SAS) AF: 0.0533 AC: 4593 AN: 86214

European-Finnish (FIN) AF: 0.0826 AC: 4340 AN: 52538

Middle Eastern (MID) AF: 0.0297 AC: 170 AN: 5728

European-Non Finnish (NFE) AF: 0.0651 AC: 72326 AN: 1111132

Other (OTH) AF: 0.0591 AC: 3567 AN: 60308

GnomAD4 genome AF: 0.0631 AC: 9605 AN: 152258 Hom.: 320 Cov.: 32 AF XY: 0.0641 AC XY: 4775 AN XY: 74452

African (AFR) AF: 0.0575 AC: 2389 AN: 41552

American (AMR) AF: 0.0734 AC: 1123 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3472

East Asian (EAS) AF: 0.0363 AC: 188 AN: 5178

South Asian (SAS) AF: 0.0541 AC: 261 AN: 4822

European-Finnish (FIN) AF: 0.0867 AC: 920 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0655 AC: 4451 AN: 68002

Other (OTH) AF: 0.0573 AC: 121 AN: 2112

Alfa AF: 0.0606 Hom.: 49

Bravo AF: 0.0625

Asia WGS AF: 0.0560 AC: 197 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 31, 2012

Leiden Open Variation Database

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker. -

not provided Benign:2

Feb 24, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Fanconi anemia complementation group P Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.92
DANN	Benign	0.75
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs112226642; hg19: chr16-3645583;