rs12933120

Variant names:

• chr16-3584745-C-A
• rs12933120
• NM_032444.4:c.4739+24G>T

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.4739+24G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,565,730 control chromosomes in the GnomAD database, including 13,336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (900 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12436 hom.)
• Consequence: SLX4 NM_032444.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.625
• Publications: 48 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=-0.82).
• BP6: Variant 16-3584745-C-A is Benign according to our data. Variant chr16-3584745-C-A is described in ClinVar as Benign. ClinVar VariationId is 929612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4	c.4739+24G>T		intron_variant	Intron 13 of 14	ENST00000294008.4	NP_115820.2
SLX4	XM_024450471.2	c.4739+24G>T		intron_variant	Intron 13 of 14		XP_024306239.1
SLX4	XM_011522715.4	c.4736+24G>T		intron_variant	Intron 13 of 14		XP_011521017.1
SLX4	XM_047434801.1	c.3737+24G>T		intron_variant	Intron 9 of 10		XP_047290757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4	c.4739+24G>T		intron_variant	Intron 13 of 14	5	NM_032444.4	ENSP00000294008.3

Frequencies

GnomAD3 genomes AF: 0.0918 AC: 13976 AN: 152184 Hom.: 897 Cov.: 32

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.0843

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.0950

Gnomad FIN AF: 0.0811

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.101 AC: 25388 AN: 251464 AF XY: 0.106

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.0592

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.00261

Gnomad FIN exome AF: 0.0834

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.127 AC: 179657 AN: 1413428 Hom.: 12436 Cov.: 24 AF XY: 0.127 AC XY: 89478 AN XY: 706046

African (AFR) AF: 0.0203 AC: 658 AN: 32408

American (AMR) AF: 0.0636 AC: 2839 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3728 AN: 25768

East Asian (EAS) AF: 0.00129 AC: 51 AN: 39496

South Asian (SAS) AF: 0.102 AC: 8704 AN: 85292

European-Finnish (FIN) AF: 0.0879 AC: 4692 AN: 53360

Middle Eastern (MID) AF: 0.146 AC: 790 AN: 5404

European-Non Finnish (NFE) AF: 0.142 AC: 151223 AN: 1068246

Other (OTH) AF: 0.119 AC: 6972 AN: 58792

GnomAD4 genome AF: 0.0918 AC: 13975 AN: 152302 Hom.: 900 Cov.: 32 AF XY: 0.0888 AC XY: 6611 AN XY: 74472

African (AFR) AF: 0.0249 AC: 1034 AN: 41576

American (AMR) AF: 0.0842 AC: 1287 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 482 AN: 3472

East Asian (EAS) AF: 0.00521 AC: 27 AN: 5184

South Asian (SAS) AF: 0.0955 AC: 461 AN: 4828

European-Finnish (FIN) AF: 0.0811 AC: 861 AN: 10620

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9431 AN: 68018

Other (OTH) AF: 0.105 AC: 221 AN: 2110

Alfa AF: 0.123 Hom.: 1912

Bravo AF: 0.0879

Asia WGS AF: 0.0390 AC: 134 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 10, 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

- -

not specified Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.3
DANN	Benign	0.38
PhyloP100		0.63
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12933120; hg19: chr16-3634746;