rs7196345

chr16-3583221-G-Achr16-3583221-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032444.4(SLX4):c.5029C>T(p.Pro1677Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000742 in 1,614,196 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. P1677H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (4 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.52

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035014153).
• BP6: Variant 16-3583221-G-A is Benign according to our data. Variant chr16-3583221-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 212220.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 = 0.0039 (594/152302) while in subpopulation AFR AF= 0.0134 (556/41558). AF 95% confidence interval is 0.0125. There are 3 homozygotes in gnomad4. There are 281 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4	c.5029C>T	p.Pro1677Ser	missense_variant	14/15	ENST00000294008.4
SLX4	XM_024450471.2	c.5029C>T	p.Pro1677Ser	missense_variant	14/15
SLX4	XM_011522715.4	c.5026C>T	p.Pro1676Ser	missense_variant	14/15
SLX4	XM_047434801.1	c.4027C>T	p.Pro1343Ser	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4	c.5029C>T	p.Pro1677Ser	missense_variant	14/15	5	NM_032444.4	P1
	ENST00000573982.1	n.284G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00389 AC: 592 AN: 152184 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00110 AC: 277 AN: 251494 Hom.: 2 AF XY: 0.000890 AC XY: 121 AN XY: 135922

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.000925

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: 0.0000967

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000412 AC: 603 AN: 1461894 Hom.: 4 Cov.: 33 AF XY: 0.000337 AC XY: 245 AN XY: 727248

Gnomad4 AFR exome AF: 0.0132

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00390 AC: 594 AN: 152302 Hom.: 3 Cov.: 33 AF XY: 0.00377 AC XY: 281 AN XY: 74472

Gnomad4 AFR AF: 0.0134

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000758 Hom.: 0

Bravo AF: 0.00436

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0114 AC: 50

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00149 AC: 181

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group P Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 15, 2021	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 28, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2022	See Variant Classification Assertion Criteria. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 19, 2019

- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.23
Dann	Benign	0.47
DEOGEN2	Benign	0.034	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.024
Sift	Benign	0.75	T
Sift4G	Benign	0.34	T
Polyphen		0.063	B
Vest4		0.063
MVP		0.048
MPC		0.057
ClinPred		0.0033	T
GERP RS		-3.3
Varity_R		0.021
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs7196345; hg19: chr16-3633222;