rs146054214

Variant names:

• chr16-3589864-G-A
• rs146054214
• NM_032444.4:c.3774C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-3589864-G-A
• chr16-3589864-G-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_032444.4(SLX4):​c.3774C>T​(p.Pro1258Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,613,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1258P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SLX4 NM_032444.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.16
• Publications: 1 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: ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 16-3589864-G-A is Benign according to our data. Variant chr16-3589864-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215952.
• BP7: Synonymous conserved (PhyloP=-1.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000802 (122/152188) while in subpopulation AFR AF = 0.00253 (105/41546). AF 95% confidence interval is 0.00214. There are 0 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.3774C>T	p.Pro1258Pro	synonymous	Exon 12 of 15	NP_115820.2	Q8IY92-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	ENST00000294008.4	TSL:5 MANE Select	c.3774C>T	p.Pro1258Pro	synonymous	Exon 12 of 15	ENSP00000294008.3	Q8IY92-1

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000246 AC: 61 AN: 248084 AF XY: 0.000208

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000900

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000714

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000123 AC: 180 AN: 1461144 Hom.: 0 Cov.: 37 AF XY: 0.000117 AC XY: 85 AN XY: 726918

African (AFR) AF: 0.00233 AC: 78 AN: 33478

American (AMR) AF: 0.000112 AC: 5 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26130

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1111980

Other (OTH) AF: 0.000265 AC: 16 AN: 60360

GnomAD4 genome AF: 0.000802 AC: 122 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000847 AC XY: 63 AN XY: 74404

African (AFR) AF: 0.00253 AC: 105 AN: 41546

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67982

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000381 Hom.: 0

Bravo AF: 0.000706

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.75
DANN	Benign	0.72
PhyloP100		-1.2

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: rs146054214; hg19: chr16-3639865; COSMIC: COSV53562351;