rs199592185

Positions:

• chr16-3583210-C-A
• chr16-3583210-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_032444.4(SLX4):​c.5040G>T​(p.Arg1680Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000712 in 1,614,170 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000070 (1 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.372

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]

ENSG00000261938 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017328382).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000854 (13/152278) while in subpopulation SAS AF= 0.00124 (6/4820). AF 95% confidence interval is 0.000542. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLX4	NM_032444.4	c.5040G>T	p.Arg1680Ser	missense_variant	14/15	ENST00000294008.4	NP_115820.2
SLX4	XM_024450471.2	c.5040G>T	p.Arg1680Ser	missense_variant	14/15		XP_024306239.1
SLX4	XM_011522715.4	c.5037G>T	p.Arg1679Ser	missense_variant	14/15		XP_011521017.1
SLX4	XM_047434801.1	c.4038G>T	p.Arg1346Ser	missense_variant	10/11		XP_047290757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4	c.5040G>T	p.Arg1680Ser	missense_variant	14/15	5	NM_032444.4	ENSP00000294008.3
ENSG00000261938	ENST00000573982.1	n.273C>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000103 AC: 26 AN: 251490 Hom.: 0 AF XY: 0.000154 AC XY: 21 AN XY: 135922

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: 0.000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000698 AC: 102 AN: 1461892 Hom.: 1 Cov.: 33 AF XY: 0.000107 AC XY: 78 AN XY: 727248

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: 0.000742

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74454

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi anemia complementation group P Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 25, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 25, 2020	A heterozygous missense variant was identified, NM_032444.2(SLX4):c.5040G>T in exon 14 of 15 of the SLX4 gene. This substitution is predicted to create a major amino acid change from arginine to serine at position 1680 of the protein, NP_115820.2(SLX4):p.(Arg1680Ser). The arginine at this position has low conservation (100 vertebrates, UCSC), and is not situated in a known functional domain. In silico software predicts this variant to be benign (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.01% (28 heterozygotes, 0 homozygotes). An alternative nucleotide change resulting in the same protein alteration to serine has been reported in the gnomAD database at a frequency of 0.004% (12 heterozygotes, 0 homozygotes). In addition, an alternative residue change at the same location has been reported in the gnomAD database at a frequency of 0.0008%. The alternative nucleotide change resulting in a serine has been previously reported as a VUS (ClinVar), and this variant has been reported in the germline of a patient with head and neck squamous cell carcinoma (Chandrasekharappa, S. et al. (2017)). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE. -

Fanconi anemia Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 16, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.5
DANN	Benign	0.92
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.90	L
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.072
Sift	Benign	0.56	T
Sift4G	Benign	0.75	T
Polyphen		0.22	B
Vest4		0.12
MutPred		0.23		Gain of phosphorylation at R1680 (P = 0.0096);
MVP		0.061
MPC		0.062
ClinPred		0.036	T
GERP RS		-0.56
Varity_R		0.10
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

Publications

LitVar

Other links and lift over

dbSNP: rs199592185; hg19: chr16-3633211;