chr16-3595606-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032444.4(SLX4):c.2012T>C(p.Leu671Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0645 in 1,613,608 control chromosomes in the GnomAD database, including 3,591 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.072 ( 408 hom., cov: 32)

Exomes 𝑓: 0.064 ( 3183 hom. )

Consequence

SLX4
NM_032444.4 missense, splice_region

Scores

Splicing: ADA: 0.00002109

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.591

Publications

22 publications found

Variant links:

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

SLX4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0028672218).

BP6

Variant 16-3595606-A-G is Benign according to our data. Variant chr16-3595606-A-G is described in ClinVar as Benign. ClinVar VariationId is 262040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0868 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032444.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	NM_032444.4	MANE Select	c.2012T>C	p.Leu671Ser	missense splice_region	Exon 9 of 15	NP_115820.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	ENST00000294008.4	TSL:5 MANE Select	c.2012T>C	p.Leu671Ser	missense splice_region	Exon 9 of 15	ENSP00000294008.3
	SLX4	ENST00000466154.5	TSL:1	n.*5T>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.0721

AC:

10971

AN:

152082

Hom.:

405

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0891

Gnomad AMI

AF:

0.0899

Gnomad AMR

AF:

0.0759

Gnomad ASJ

AF:

0.0188

Gnomad EAS

AF:

0.0365

Gnomad SAS

AF:

0.0536

Gnomad FIN

AF:

0.0867

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0656

Gnomad OTH

AF:

0.0669

GnomAD2 exomes

AF:

0.0636

AC:

15922

AN:

250160

AF XY:

0.0617

show subpopulations

Gnomad AFR exome

AF:

0.0894

Gnomad AMR exome

AF:

0.0725

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.0349

Gnomad FIN exome

AF:

0.0874

Gnomad NFE exome

AF:

0.0650

Gnomad OTH exome

AF:

0.0539

GnomAD4 exome

AF:

0.0637

AC:

93133

AN:

1461408

Hom.:

3183

Cov.:

AF XY:

0.0629

AC XY:

45760

AN XY:

727010

show subpopulations

African (AFR)

AF:

0.0862

AC:

2887

AN:

33476

American (AMR)

AF:

0.0698

AC:

3120

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0189

AC:

494

AN:

26116

East Asian (EAS)

AF:

0.0315

AC:

1251

AN:

39700

South Asian (SAS)

AF:

0.0535

AC:

4617

AN:

86250

European-Finnish (FIN)

AF:

0.0827

AC:

4389

AN:

53090

Middle Eastern (MID)

AF:

0.0314

AC:

181

AN:

5764

European-Non Finnish (NFE)

AF:

0.0652

AC:

72497

AN:

1111924

Other (OTH)

AF:

0.0612

AC:

3697

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

4928

9856

14783

19711

24639

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2670

5340

8010

10680

13350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0722

AC:

10984

AN:

152200

Hom.:

408

Cov.:

AF XY:

0.0727

AC XY:

5409

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0892

AC:

3704

AN:

41530

American (AMR)

AF:

0.0756

AC:

1156

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0188

AC:

AN:

3464

East Asian (EAS)

AF:

0.0364

AC:

188

AN:

5168

South Asian (SAS)

AF:

0.0545

AC:

263

AN:

4824

European-Finnish (FIN)

AF:

0.0867

AC:

920

AN:

10606

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0656

AC:

4460

AN:

67990

Other (OTH)

AF:

0.0662

AC:

140

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

530

1060

1591

2121

2651

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

248

372

496

620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0643

Hom.:

290

Bravo

AF:

0.0731

TwinsUK

AF:

0.0599

AC:

222

ALSPAC

AF:

0.0620

AC:

239

ESP6500AA

AF:

0.0915

AC:

402

ESP6500EA

AF:

0.0677

AC:

582

ExAC

AF:

0.0654

AC:

7939

Asia WGS

AF:

0.0570

AC:

201

AN:

3478

EpiCase

AF:

0.0570

EpiControl

AF:

0.0586

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fanconi anemia complementation group P (3)

not provided (2)

not specified (2)

Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.82

CADD

Benign

8.3

(source)

DANN

Benign

0.19

DEOGEN2

Benign

0.018

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.00081

LIST_S2

Benign

0.10

MetaRNN

Benign

0.0029

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.2

PhyloP100

0.59

PrimateAI

Benign

0.36

PROVEAN

Benign

2.4

REVEL

Benign

0.044

Sift

Benign

0.59

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.076

MPC

0.073

ClinPred

0.00043

GERP RS

0.88

Varity_R

0.16

gMVP

0.26

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000021

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over