16-3598074-G-C

Variant names:

• chr16-3598074-G-C
• rs59622164
• NM_032444.4:c.1164-75C>G

Variant summary

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

The ENST00000294008.4(SLX4):​c.1164-75C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0623 in 1,561,208 control chromosomes in the GnomAD database, including 3,260 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (292 hom., cov: 33)
  • Exomes 𝑓: 0.063 (2968 hom.)
• Consequence: SLX4 ENST00000294008.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.497
• Publications: 7 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 (BayesDel_noAF=-0.88).
• BP6: Variant 16-3598074-G-C is Benign according to our data. Variant chr16-3598074-G-C is described in ClinVar as Benign. ClinVar VariationId is 1250198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0678 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000294008.4. 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.1164-75C>G		intron	N/A	NP_115820.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	ENST00000294008.4	TSL:5 MANE Select	c.1164-75C>G		intron	N/A	ENSP00000294008.3
	SLX4	ENST00000466154.5	TSL:1	n.2385-75C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0591 AC: 8998 AN: 152190 Hom.: 292 Cov.: 33

Gnomad AFR AF: 0.0437

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0716

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0364

Gnomad SAS AF: 0.0528

Gnomad FIN AF: 0.0865

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0656

Gnomad OTH AF: 0.0549

GnomAD4 exome AF: 0.0626 AC: 88200 AN: 1408900 Hom.: 2968 AF XY: 0.0620 AC XY: 43614 AN XY: 703794

African (AFR) AF: 0.0426 AC: 1380 AN: 32368

American (AMR) AF: 0.0676 AC: 2991 AN: 44228

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 489 AN: 25814

East Asian (EAS) AF: 0.0315 AC: 1240 AN: 39402

South Asian (SAS) AF: 0.0533 AC: 4510 AN: 84574

European-Finnish (FIN) AF: 0.0832 AC: 4377 AN: 52616

Middle Eastern (MID) AF: 0.0287 AC: 162 AN: 5636

European-Non Finnish (NFE) AF: 0.0654 AC: 69655 AN: 1065728

Other (OTH) AF: 0.0580 AC: 3396 AN: 58534

GnomAD4 genome AF: 0.0591 AC: 8996 AN: 152308 Hom.: 292 Cov.: 33 AF XY: 0.0605 AC XY: 4505 AN XY: 74470

African (AFR) AF: 0.0436 AC: 1814 AN: 41566

American (AMR) AF: 0.0713 AC: 1091 AN: 15300

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

East Asian (EAS) AF: 0.0363 AC: 188 AN: 5184

South Asian (SAS) AF: 0.0537 AC: 259 AN: 4824

European-Finnish (FIN) AF: 0.0865 AC: 918 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0656 AC: 4459 AN: 68024

Other (OTH) AF: 0.0543 AC: 115 AN: 2116

Alfa AF: 0.0316 Hom.: 17

Bravo AF: 0.0574

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.37
DANN	Benign	0.45
PhyloP100		-0.50
Mutation Taster		=100/0	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: rs59622164; hg19: chr16-3648075;