Genetic Variant NM_032444.4:c.1925-30G>A (chr16-3595723-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032444.4(SLX4):c.1925-30G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,609,636 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 11 hom. )

Consequence

SLX4
NM_032444.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.04

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 16-3595723-C-T is Benign according to our data. Variant chr16-3595723-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 262039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3595723-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00626 (954/152298) while in subpopulation AFR AF= 0.0176 (733/41568). AF 95% confidence interval is 0.0166. There are 9 homozygotes in gnomad4. There are 459 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4 link	c.1925-30G>A		intron_variant	Intron 8 of 14	ENST00000294008.4	NP_115820.2	Q8IY92-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4 link	c.1925-30G>A		intron_variant	Intron 8 of 14	5	NM_032444.4	ENSP00000294008.3		Q8IY92-1
SLX4	ENST00000466154.5 link	n.3146-30G>A		intron_variant	Intron 6 of 6	1

Frequencies

GnomAD3 genomes

AF:

0.00623

AC:

948

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0175

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00175

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00302

AC:

731

AN:

241944

Hom.:

AF XY:

0.00273

AC XY:

359

AN XY:

131694

show subpopulations

Gnomad AFR exome

AF:

0.0170

Gnomad AMR exome

AF:

0.00416

Gnomad ASJ exome

AF:

0.00162

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00251

Gnomad FIN exome

AF:

0.0000490

Gnomad NFE exome

AF:

0.00198

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00206

AC:

2998

AN:

1457338

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

1508

AN XY:

724998

show subpopulations

Gnomad4 AFR exome

AF:

0.0175

Gnomad4 AMR exome

AF:

0.00400

Gnomad4 ASJ exome

AF:

0.00130

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00324

Gnomad4 FIN exome

AF:

0.000287

Gnomad4 NFE exome

AF:

0.00148

Gnomad4 OTH exome

AF:

0.00324

GnomAD4 genome

AF:

0.00626

AC:

954

AN:

152298

Hom.:

Cov.:

AF XY:

0.00616

AC XY:

459

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0176

Gnomad4 AMR

AF:

0.00418

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00353

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00175

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00144

Hom.:

Bravo

AF:

0.00654

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 31, 2012

Leiden Open Variation Database

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker. -

not provided

Benign:2

Jun 21, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.20

DANN

Benign

0.54

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over