rs115694169

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032444.4(SLX4):c.1153C>A(p.Pro385Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,613,620 control chromosomes in the GnomAD database, including 40 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P385P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0092 ( 20 hom., cov: 31)

Exomes 𝑓: 0.0024 ( 20 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.209

Publications

10 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: ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
familial ovarian cancer
Inheritance: Unknown 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=0.0049327016).

BP6

Variant 16-3600989-G-T is Benign according to our data. Variant chr16-3600989-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262031.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 = 0.00918 (1397/152196) while in subpopulation AFR AF = 0.0277 (1151/41504). AF 95% confidence interval is 0.0264. There are 20 homozygotes in GnomAd4. There are 645 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AR,AD gene

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.1153C>A	p.Pro385Thr	missense	Exon 5 of 15	NP_115820.2	Q8IY92-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLX4	ENST00000294008.4	TSL:5 MANE Select	c.1153C>A	p.Pro385Thr	missense	Exon 5 of 15	ENSP00000294008.3	Q8IY92-1
SLX4	ENST00000466154.5	TSL:1	n.2374C>A		non_coding_transcript_exon	Exon 3 of 7
SLX4	ENST00000486524.1	TSL:2	n.2707C>A		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

AF:

0.00915

AC:

1392

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0277

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00179

Gnomad OTH

AF:

0.00911

GnomAD2 exomes

AF:

0.00376

AC:

942

AN:

250206

AF XY:

0.00318

show subpopulations

Gnomad AFR exome

AF:

0.0280

Gnomad AMR exome

AF:

0.00463

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00185

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00236

AC:

3449

AN:

1461424

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

1678

AN XY:

727024

show subpopulations

African (AFR)

AF:

0.0291

AC:

974

AN:

33474

American (AMR)

AF:

0.00454

AC:

203

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00134

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00314

AC:

271

AN:

86240

European-Finnish (FIN)

AF:

0.000301

AC:

AN:

53174

Middle Eastern (MID)

AF:

0.0134

AC:

AN:

5606

European-Non Finnish (NFE)

AF:

0.00149

AC:

1657

AN:

1111994

Other (OTH)

AF:

0.00361

AC:

218

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

199

398

596

795

994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.00918

AC:

1397

AN:

152196

Hom.:

Cov.:

AF XY:

0.00867

AC XY:

645

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0277

AC:

1151

AN:

41504

American (AMR)

AF:

0.00536

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00353

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00179

AC:

122

AN:

68022

Other (OTH)

AF:

0.00901

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

136

203

271

339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00573

Hom.:

Bravo

AF:

0.00987

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.0207

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00432

AC:

524

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00354

EpiControl

AF:

0.00279

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Fanconi anemia complementation group P (2)

Fanconi anemia (1)

Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.48

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.052

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.27

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.6

PhyloP100

-0.21

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.1

REVEL

Benign

0.044

Sift

Benign

0.45

Sift4G

Benign

0.38

Polyphen

0.031

Vest4

0.054

MVP

0.12

MPC

0.15

ClinPred

0.0020

GERP RS

0.013

Varity_R

0.034

gMVP

0.24

Mutation Taster

=99/1

polymorphism

(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