16-3608958-G-C

Variant summary

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

The NM_032444.4(SLX4):c.7C>G(p.Leu3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L3R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.102

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=0.061974376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.7C>G	p.Leu3Val	missense_variant	2/15	ENST00000294008.4
SLX4	XM_024450471.2	c.7C>G	p.Leu3Val	missense_variant	2/15
SLX4	XM_011522715.4	c.7C>G	p.Leu3Val	missense_variant	2/15
SLX4	XR_007064923.1	n.656C>G		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.7C>G	p.Leu3Val	missense_variant	2/15	5	NM_032444.4	P1
SLX4	ENST00000466154.5	n.302C>G		non_coding_transcript_exon_variant	1/7	1
SLX4	ENST00000486524.1	n.635C>G		non_coding_transcript_exon_variant	2/4	2
SLX4	ENST00000697859.1	n.629C>G		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250154 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135376

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460666 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726670

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.45
Dann	Benign	0.78
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.071
Sift	Pathogenic	0.0	D
Sift4G	Benign	1.0	T
Polyphen		0.81	P
Vest4		0.13
MutPred		0.15		Gain of sheet (P = 0.0344);
MVP		0.16
MPC		0.056
ClinPred		0.089	T
GERP RS		0.65
Varity_R		0.061
gMVP		0.0098

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

Publications

LitVar

Other links and lift over

dbSNP: rs751472980; hg19: chr16-3658959;