16-3590783-G-A

Variant names:

• chr16-3590783-G-A
• rs78637028
• NM_032444.4:c.2855C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032444.4(SLX4):​c.2855C>T​(p.Ala952Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0602 in 1,613,928 control chromosomes in the GnomAD database, including 3,253 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A952T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.050 (238 hom., cov: 33)
  • Exomes 𝑓: 0.061 (3015 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.432
• Publications: 14 publications found

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]

SLX4 Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group P

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017929375).
• BP6: Variant 16-3590783-G-A is Benign according to our data. Variant chr16-3590783-G-A is described in ClinVar as Benign. ClinVar VariationId is 262045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4	c.2855C>T	p.Ala952Val	missense_variant	Exon 12 of 15	ENST00000294008.4	NP_115820.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4	c.2855C>T	p.Ala952Val	missense_variant	Exon 12 of 15	5	NM_032444.4	ENSP00000294008.3

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7578 AN: 152150 Hom.: 238 Cov.: 33

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0691

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0362

Gnomad SAS AF: 0.0526

Gnomad FIN AF: 0.0858

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0651

Gnomad OTH AF: 0.0483

GnomAD2 exomes AF: 0.0582 AC: 14609 AN: 251138 AF XY: 0.0578

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.0690

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.0355

Gnomad FIN exome AF: 0.0881

Gnomad NFE exome AF: 0.0651

Gnomad OTH exome AF: 0.0502

GnomAD4 exome AF: 0.0613 AC: 89633 AN: 1461660 Hom.: 3015 Cov.: 37 AF XY: 0.0609 AC XY: 44248 AN XY: 727156

African (AFR) AF: 0.00914 AC: 306 AN: 33480

American (AMR) AF: 0.0651 AC: 2909 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 494 AN: 26136

East Asian (EAS) AF: 0.0317 AC: 1259 AN: 39700

South Asian (SAS) AF: 0.0531 AC: 4581 AN: 86258

European-Finnish (FIN) AF: 0.0829 AC: 4411 AN: 53210

Middle Eastern (MID) AF: 0.0276 AC: 159 AN: 5768

European-Non Finnish (NFE) AF: 0.0649 AC: 72179 AN: 1111996

Other (OTH) AF: 0.0552 AC: 3335 AN: 60394

GnomAD4 genome AF: 0.0497 AC: 7575 AN: 152268 Hom.: 238 Cov.: 33 AF XY: 0.0513 AC XY: 3817 AN XY: 74446

African (AFR) AF: 0.0118 AC: 489 AN: 41566

American (AMR) AF: 0.0688 AC: 1053 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3472

East Asian (EAS) AF: 0.0361 AC: 187 AN: 5180

South Asian (SAS) AF: 0.0534 AC: 258 AN: 4828

European-Finnish (FIN) AF: 0.0858 AC: 909 AN: 10598

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0651 AC: 4426 AN: 68000

Other (OTH) AF: 0.0478 AC: 101 AN: 2112

Alfa AF: 0.0563 Hom.: 610

Bravo AF: 0.0465

TwinsUK AF: 0.0599 AC: 222

ALSPAC AF: 0.0612 AC: 236

ESP6500AA AF: 0.0146 AC: 64

ESP6500EA AF: 0.0647 AC: 556

ExAC AF: 0.0583 AC: 7073

Asia WGS AF: 0.0500 AC: 174 AN: 3478

EpiCase AF: 0.0567

EpiControl AF: 0.0583

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group P Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 24, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia Benign:1

Feb 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.43
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.027
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.045	D
Polyphen		0.93	P
Vest4		0.033
MPC		0.072
ClinPred		0.010	T
GERP RS		3.2
Varity_R		0.039
gMVP		0.15
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs78637028; hg19: chr16-3640784; COSMIC: COSV53567787; COSMIC: COSV53567787;