16-3590476-C-T

Variant names:

• chr16-3590476-C-T
• rs76488917
• NM_032444.4:c.3162G>A

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.3162G>A​(p.Ser1054Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,614,034 control chromosomes in the GnomAD database, including 1,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1054S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.036 (185 hom., cov: 33)
  • Exomes 𝑓: 0.023 (1070 hom.)
• Consequence: SLX4 NM_032444.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -5.33
• Publications: 9 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 16-3590476-C-T is Benign according to our data. Variant chr16-3590476-C-T is described in ClinVar as Benign. ClinVar VariationId is 262046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.111 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.3162G>A	p.Ser1054Ser	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.3162G>A	p.Ser1054Ser	synonymous	Exon 12 of 15	ENSP00000294008.3	Q8IY92-1

Frequencies

GnomAD3 genomes AF: 0.0364 AC: 5532 AN: 152136 Hom.: 184 Cov.: 33

Gnomad AFR AF: 0.0795

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0448

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0320

GnomAD2 exomes AF: 0.0329 AC: 8257 AN: 251130 AF XY: 0.0365

Gnomad AFR exome AF: 0.0786

Gnomad AMR exome AF: 0.0144

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.0497

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.0253

GnomAD4 exome AF: 0.0225 AC: 32940 AN: 1461780 Hom.: 1070 Cov.: 37 AF XY: 0.0251 AC XY: 18262 AN XY: 727164

African (AFR) AF: 0.0890 AC: 2981 AN: 33478

American (AMR) AF: 0.0151 AC: 676 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0169 AC: 442 AN: 26132

East Asian (EAS) AF: 0.0474 AC: 1880 AN: 39700

South Asian (SAS) AF: 0.116 AC: 9968 AN: 86258

European-Finnish (FIN) AF: 0.0131 AC: 699 AN: 53384

Middle Eastern (MID) AF: 0.0348 AC: 201 AN: 5768

European-Non Finnish (NFE) AF: 0.0128 AC: 14224 AN: 1111948

Other (OTH) AF: 0.0309 AC: 1869 AN: 60390

GnomAD4 genome AF: 0.0364 AC: 5535 AN: 152254 Hom.: 185 Cov.: 33 AF XY: 0.0375 AC XY: 2788 AN XY: 74434

African (AFR) AF: 0.0795 AC: 3301 AN: 41536

American (AMR) AF: 0.0235 AC: 360 AN: 15290

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

East Asian (EAS) AF: 0.0451 AC: 233 AN: 5164

South Asian (SAS) AF: 0.119 AC: 575 AN: 4826

European-Finnish (FIN) AF: 0.0132 AC: 140 AN: 10618

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0112 AC: 764 AN: 68028

Other (OTH) AF: 0.0317 AC: 67 AN: 2116

Alfa AF: 0.0288 Hom.: 104

Bravo AF: 0.0381

EpiCase AF: 0.0152

EpiControl AF: 0.0148

ClinVar

ClinVar submissions

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	-0.73
CADD	Benign	0.54
DANN	Benign	0.55
PhyloP100		-5.3
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: rs76488917; hg19: chr16-3640477;