rs112511042

Variant names:

• chr16-3600990-T-C
• rs112511042
• NM_032444.4:c.1152A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032444.4(SLX4):​c.1152A>G​(p.Pro384Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0628 in 1,613,138 control chromosomes in the GnomAD database, including 3,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (318 hom., cov: 31)
  • Exomes 𝑓: 0.063 (3089 hom.)
• Consequence: SLX4 NM_032444.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.51
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 16-3600990-T-C is Benign according to our data. Variant chr16-3600990-T-C is described in ClinVar as Benign. ClinVar VariationId is 262030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.07 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032444.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	NM_032444.4	MANE Select	c.1152A>G	p.Pro384Pro	synonymous	Exon 5 of 15	NP_115820.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	ENST00000294008.4	TSL:5 MANE Select	c.1152A>G	p.Pro384Pro	synonymous	Exon 5 of 15	ENSP00000294008.3
	SLX4	ENST00000466154.5	TSL:1	n.2373A>G		non_coding_transcript_exon	Exon 3 of 7
	SLX4	ENST00000486524.1	TSL:2	n.2706A>G		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.0632 AC: 9606 AN: 152032 Hom.: 316 Cov.: 31

Gnomad AFR AF: 0.0577

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0737

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0366

Gnomad SAS AF: 0.0531

Gnomad FIN AF: 0.0863

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0655

Gnomad OTH AF: 0.0584

GnomAD2 exomes AF: 0.0613 AC: 15331 AN: 250078 AF XY: 0.0601

Gnomad AFR exome AF: 0.0573

Gnomad AMR exome AF: 0.0713

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.0350

Gnomad FIN exome AF: 0.0873

Gnomad NFE exome AF: 0.0650

Gnomad OTH exome AF: 0.0517

GnomAD4 exome AF: 0.0628 AC: 91737 AN: 1460988 Hom.: 3089 Cov.: 31 AF XY: 0.0621 AC XY: 45129 AN XY: 726822

African (AFR) AF: 0.0580 AC: 1940 AN: 33466

American (AMR) AF: 0.0682 AC: 3049 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 494 AN: 26136

East Asian (EAS) AF: 0.0319 AC: 1266 AN: 39700

South Asian (SAS) AF: 0.0533 AC: 4594 AN: 86228

European-Finnish (FIN) AF: 0.0829 AC: 4408 AN: 53166

Middle Eastern (MID) AF: 0.0291 AC: 163 AN: 5598

European-Non Finnish (NFE) AF: 0.0650 AC: 72263 AN: 1111624

Other (OTH) AF: 0.0590 AC: 3560 AN: 60358

GnomAD4 genome AF: 0.0632 AC: 9616 AN: 152150 Hom.: 318 Cov.: 31 AF XY: 0.0643 AC XY: 4784 AN XY: 74396

African (AFR) AF: 0.0578 AC: 2400 AN: 41498

American (AMR) AF: 0.0735 AC: 1124 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3468

East Asian (EAS) AF: 0.0365 AC: 189 AN: 5174

South Asian (SAS) AF: 0.0539 AC: 260 AN: 4820

European-Finnish (FIN) AF: 0.0863 AC: 913 AN: 10582

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

European-Non Finnish (NFE) AF: 0.0655 AC: 4456 AN: 68002

Other (OTH) AF: 0.0578 AC: 122 AN: 2112

Alfa AF: 0.0614 Hom.: 147

Bravo AF: 0.0626

Asia WGS AF: 0.0570 AC: 198 AN: 3478

EpiCase AF: 0.0568

EpiControl AF: 0.0584

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fanconi anemia complementation group P (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.079
DANN	Benign	0.34
PhyloP100		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs112511042; hg19: chr16-3650991; COSMIC: COSV108101261;