rs114016359

Variant names:

• chr16-3596322-G-A
• rs114016359
• NM_032444.4:c.1755C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-3596322-G-A
• chr16-3596322-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032444.4(SLX4):​c.1755C>T​(p.Pro585Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,584,644 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P585P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0063 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (10 hom.)
• Consequence: SLX4 NM_032444.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0750
• Publications: 3 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=-0.85).
• BP6: Variant 16-3596322-G-A is Benign according to our data. Variant chr16-3596322-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262037.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 = 0.00628 (956/152328) while in subpopulation AFR AF = 0.0177 (734/41578). AF 95% confidence interval is 0.0166. There are 9 homozygotes in GnomAd4. There are 457 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

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.1755C>T	p.Pro585Pro	synonymous	Exon 8 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.1755C>T	p.Pro585Pro	synonymous	Exon 8 of 15	ENSP00000294008.3
	SLX4	ENST00000466154.5	TSL:1	n.2976C>T		non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 950 AN: 152210 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00279 AC: 551 AN: 197514 AF XY: 0.00264

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.00352

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000588

Gnomad NFE exome AF: 0.00181

Gnomad OTH exome AF: 0.00430

GnomAD4 exome AF: 0.00203 AC: 2905 AN: 1432316 Hom.: 10 Cov.: 32 AF XY: 0.00205 AC XY: 1457 AN XY: 710034

African (AFR) AF: 0.0175 AC: 577 AN: 33052

American (AMR) AF: 0.00370 AC: 149 AN: 40306

Ashkenazi Jewish (ASJ) AF: 0.00130 AC: 33 AN: 25426

East Asian (EAS) AF: 0.00 AC: 0 AN: 38460

South Asian (SAS) AF: 0.00312 AC: 258 AN: 82596

European-Finnish (FIN) AF: 0.000302 AC: 15 AN: 49662

Middle Eastern (MID) AF: 0.0128 AC: 71 AN: 5530

European-Non Finnish (NFE) AF: 0.00146 AC: 1605 AN: 1098070

Other (OTH) AF: 0.00333 AC: 197 AN: 59214

GnomAD4 genome AF: 0.00628 AC: 956 AN: 152328 Hom.: 9 Cov.: 32 AF XY: 0.00614 AC XY: 457 AN XY: 74488

African (AFR) AF: 0.0177 AC: 734 AN: 41578

American (AMR) AF: 0.00425 AC: 65 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00172 AC: 117 AN: 68018

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.000902 Hom.: 0

Bravo AF: 0.00655

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Fanconi anemia (1)
-	-	1	Fanconi anemia complementation group P (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.2
DANN	Benign	0.77
PhyloP100		-0.075
Mutation Taster		=100/0	polymorphism

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: rs114016359; hg19: chr16-3646323;