16-3606697-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032444.4(SLX4):c.537G>C(p.Glu179Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLX4 NM_032444.4 missense, splice_region
• Scores: Splicing: ADA: 0.00006681
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0890

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046674162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.537G>C	p.Glu179Asp	missense_variant, splice_region_variant	3/15	ENST00000294008.4
SLX4	XM_024450471.2	c.537G>C	p.Glu179Asp	missense_variant, splice_region_variant	3/15
SLX4	XM_011522715.4	c.537G>C	p.Glu179Asp	missense_variant, splice_region_variant	3/15
SLX4	XR_007064923.1	n.1186G>C		splice_region_variant, non_coding_transcript_exon_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.537G>C	p.Glu179Asp	missense_variant, splice_region_variant	3/15	5	NM_032444.4	P1
SLX4	ENST00000466154.5	n.832G>C		splice_region_variant, non_coding_transcript_exon_variant	2/7	1
SLX4	ENST00000486524.1	n.1165G>C		splice_region_variant, non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	7.1
Dann	Uncertain	0.98
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.082
Sift	Benign	0.036	D
Sift4G	Benign	0.17	T
Polyphen		0.16	B
Vest4		0.17
MutPred		0.061		Gain of loop (P = 0.0851);
MVP		0.18
MPC		0.052
ClinPred		0.042	T
GERP RS		0.71
Varity_R		0.13
gMVP		0.097

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000067
dbscSNV1_RF	Benign	0.012
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

Publications

LitVar

Other links and lift over

dbSNP: rs758789462; hg19: chr16-3656698;