rs141567438

chr16-3589377-T-Achr16-3589377-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_032444.4(SLX4):c.4261A>T(p.Ile1421Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000948 in 1,590,344 control chromosomes in the GnomAD database, including 2 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 0.00063 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (2 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: -2.41

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023132086).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000627 (95/151508) while in subpopulation NFE AF= 0.00108 (73/67818). AF 95% confidence interval is 0.000878. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. Median coverage is 32. 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	UniProt
SLX4	NM_032444.4	c.4261A>T	p.Ile1421Phe	missense_variant	12/15	ENST00000294008.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.4261A>T	p.Ile1421Phe	missense_variant	12/15	5	NM_032444.4	P1

Frequencies

GnomAD3 genomes AF: 0.000628 AC: 95 AN: 151388 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000763

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00108

Gnomad OTH AF: 0.000962

GnomAD3 exomes AF: 0.000544 AC: 130 AN: 239028 Hom.: 0 AF XY: 0.000600 AC XY: 78 AN XY: 129996

Gnomad AFR exome AF: 0.000134

Gnomad AMR exome AF: 0.0000902

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000393

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.000981 AC: 1412 AN: 1438836 Hom.: 2 Cov.: 38 AF XY: 0.000907 AC XY: 646 AN XY: 712294

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.0000463

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.000527

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.000624

GnomAD4 genome AF: 0.000627 AC: 95 AN: 151508 Hom.: 0 Cov.: 32 AF XY: 0.000648 AC XY: 48 AN XY: 74054

Gnomad4 AFR AF: 0.000218

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000763

Gnomad4 NFE AF: 0.00108

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.000578

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000947 AC: 8

ExAC AF: 0.000578 AC: 70

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2016	- -

not specified Uncertain:1 Benign:1

Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 31, 2012	Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 02, 2018	- -

Fanconi anemia Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Apr 22, 2021	- -

Fanconi anemia complementation group P Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 03, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	3.7
Dann	Benign	0.93
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.078
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.059	T
Polyphen		0.93	P
Vest4		0.22
MVP		0.085
MPC		0.18
ClinPred		0.034	T
GERP RS		-4.0
Varity_R		0.086
gMVP		0.27

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: rs141567438; hg19: chr16-3639378;