rs140892471

Positions:

• chr16-3589397-G-A
• chr16-3589397-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_032444.4(SLX4):​c.4241C>T​(p.Pro1414Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000521 in 1,599,442 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1414A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.38

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 Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.002541095).
• BP6: Variant 16-3589397-G-A is Benign according to our data. Variant chr16-3589397-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 212219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0028 (427/152278) while in subpopulation AFR AF= 0.00968 (402/41530). AF 95% confidence interval is 0.0089. There are 0 homozygotes in gnomad4. There are 209 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.4241C>T	p.Pro1414Leu	missense_variant	12/15	ENST00000294008.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.4241C>T	p.Pro1414Leu	missense_variant	12/15	5	NM_032444.4	P1

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00971

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000718 AC: 176 AN: 245156 Hom.: 1 AF XY: 0.000631 AC XY: 84 AN XY: 133182

Gnomad AFR exome AF: 0.00941

Gnomad AMR exome AF: 0.000816

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000281 AC: 407 AN: 1447164 Hom.: 1 Cov.: 38 AF XY: 0.000226 AC XY: 162 AN XY: 717334

Gnomad4 AFR exome AF: 0.00913

Gnomad4 AMR exome AF: 0.000857

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000163

Gnomad4 OTH exome AF: 0.000754

GnomAD4 genome AF: 0.00280 AC: 427 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74462

Gnomad4 AFR AF: 0.00968

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000385 Hom.: 1

Bravo AF: 0.00310

ESP6500AA AF: 0.00608 AC: 26

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.000777 AC: 94

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 11, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.6
DANN	Benign	0.62
DEOGEN2	Benign	0.038	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.7	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	2.9	N
REVEL	Benign	0.047
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.056
MVP		0.067
MPC		0.056
ClinPred		0.0039	T
GERP RS		3.4
Varity_R		0.019
gMVP		0.089

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: rs140892471; hg19: chr16-3639398;