16-3589305-G-C

Variant names:

• chr16-3589305-G-C
• rs777967898
• NM_032444.4:c.4333C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032444.4(SLX4):​c.4333C>G​(p.Arg1445Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,430,096 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1445Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.851
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24291211).

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.4333C>G	p.Arg1445Gly	missense	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.4333C>G	p.Arg1445Gly	missense	Exon 12 of 15	ENSP00000294008.3	Q8IY92-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000890 AC: 2 AN: 224676 AF XY: 0.00000827

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1430096 Hom.: 0 Cov.: 38 AF XY: 0.00000141 AC XY: 1 AN XY: 707754

African (AFR) AF: 0.00 AC: 0 AN: 32526

American (AMR) AF: 0.00 AC: 0 AN: 41774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23820

East Asian (EAS) AF: 0.00 AC: 0 AN: 39388

South Asian (SAS) AF: 0.00 AC: 0 AN: 81072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5584

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1095304

Other (OTH) AF: 0.00 AC: 0 AN: 58900

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.031
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.85
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.089
Sift	Benign	0.090	T
Sift4G	Benign	0.15	T
Polyphen		0.99	D
Vest4		0.36
MutPred		0.14		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.31
MPC		0.36
ClinPred		0.94	D
GERP RS		3.5
Varity_R		0.14
gMVP		0.20

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: rs777967898; hg19: chr16-3639306;