chr16-3600986-T-C

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.1156A>G(p.Met386Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0628 in 1,613,030 control chromosomes in the GnomAD database, including 3,410 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M386T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.063 ( 320 hom., cov: 32)

Exomes 𝑓: 0.063 ( 3090 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.353

Publications

18 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=0.0031724274).

BP6

Variant 16-3600986-T-C is Benign according to our data. Variant chr16-3600986-T-C is described in ClinVar as Benign. ClinVar VariationId is 262032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0701 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	NM_032444.4	MANE Select	c.1156A>G	p.Met386Val	missense	Exon 5 of 15	NP_115820.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLX4	ENST00000294008.4	TSL:5 MANE Select	c.1156A>G	p.Met386Val	missense	Exon 5 of 15	ENSP00000294008.3
SLX4	ENST00000466154.5	TSL:1	n.2377A>G		non_coding_transcript_exon	Exon 3 of 7
SLX4	ENST00000486524.1	TSL:2	n.2710A>G		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

AF:

0.0632

AC:

9607

AN:

152030

Hom.:

319

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0577

Gnomad AMI

AF:

0.0899

Gnomad AMR

AF:

0.0739

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.0366

Gnomad SAS

AF:

0.0532

Gnomad FIN

AF:

0.0863

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0655

Gnomad OTH

AF:

0.0580

GnomAD2 exomes

AF:

0.0612

AC:

15305

AN:

250000

AF XY:

0.0601

show subpopulations

Gnomad AFR exome

AF:

0.0570

Gnomad AMR exome

AF:

0.0713

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.0349

Gnomad FIN exome

AF:

0.0871

Gnomad NFE exome

AF:

0.0649

Gnomad OTH exome

AF:

0.0517

GnomAD4 exome

AF:

0.0628

AC:

91682

AN:

1460882

Hom.:

3090

Cov.:

AF XY:

0.0621

AC XY:

45108

AN XY:

726780

show subpopulations

African (AFR)

AF:

0.0579

AC:

1937

AN:

33462

American (AMR)

AF:

0.0682

AC:

3049

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0189

AC:

494

AN:

26136

East Asian (EAS)

AF:

0.0319

AC:

1266

AN:

39700

South Asian (SAS)

AF:

0.0533

AC:

4593

AN:

86228

European-Finnish (FIN)

AF:

0.0829

AC:

4405

AN:

53168

Middle Eastern (MID)

AF:

0.0291

AC:

163

AN:

5604

European-Non Finnish (NFE)

AF:

0.0650

AC:

72221

AN:

1111536

Other (OTH)

AF:

0.0589

AC:

3554

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

4926

9851

14777

19702

24628

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2640

5280

7920

10560

13200

<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:

0.0632

AC:

9616

AN:

152148

Hom.:

320

Cov.:

AF XY:

0.0643

AC XY:

4784

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.0578

AC:

2402

AN:

41522

American (AMR)

AF:

0.0736

AC:

1125

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

AN:

3468

East Asian (EAS)

AF:

0.0365

AC:

189

AN:

5176

South Asian (SAS)

AF:

0.0541

AC:

261

AN:

4824

European-Finnish (FIN)

AF:

0.0863

AC:

912

AN:

10568

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0655

AC:

4454

AN:

67998

Other (OTH)

AF:

0.0574

AC:

121

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

477

955

1432

1910

2387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<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:

0.0618

Hom.:

906

Bravo

AF:

0.0626

TwinsUK

AF:

0.0591

AC:

219

ALSPAC

AF:

0.0618

AC:

238

ESP6500AA

AF:

0.0617

AC:

271

ESP6500EA

AF:

0.0669

AC:

575

ExAC

AF:

0.0623

AC:

7562

Asia WGS

AF:

0.0570

AC:

198

AN:

3478

EpiCase

AF:

0.0568

EpiControl

AF:

0.0583

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

0.049

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.51

(source)

DANN

Benign

0.36

DEOGEN2

Benign

0.014

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.14

MetaRNN

Benign

0.0032

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.4

PhyloP100

0.35

PrimateAI

Benign

0.35

PROVEAN

Benign

0.65

REVEL

Benign

0.051

Sift

Benign

0.65

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.022

MPC

0.056

ClinPred

0.00079

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.042

gMVP

0.18

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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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