chr16-3600969-G-A

Variant names:

• chr16-3600969-G-A
• rs80116508
• NM_032444.4:c.1163+10C>T

Variant summary

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

The NM_032444.4(SLX4):​c.1163+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0635 in 1,611,776 control chromosomes in the GnomAD database, including 3,489 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (358 hom., cov: 31)
  • Exomes 𝑓: 0.063 (3131 hom.)
• Consequence: SLX4 NM_032444.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.330
• Publications: 12 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: 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 16-3600969-G-A is Benign according to our data. Variant chr16-3600969-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0718 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.1163+10C>T		intron	N/A	NP_115820.2	Q8IY92-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	ENST00000294008.4	TSL:5 MANE Select	c.1163+10C>T		intron	N/A	ENSP00000294008.3	Q8IY92-1
	SLX4	ENST00000466154.5	TSL:1	n.2384+10C>T		intron	N/A
	SLX4	ENST00000486524.1	TSL:2	n.2727C>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.0669 AC: 10167 AN: 151930 Hom.: 357 Cov.: 31

Gnomad AFR AF: 0.0705

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0757

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0367

Gnomad SAS AF: 0.0528

Gnomad FIN AF: 0.0867

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0656

Gnomad OTH AF: 0.0598

GnomAD2 exomes AF: 0.0621 AC: 15459 AN: 249084 AF XY: 0.0607

Gnomad AFR exome AF: 0.0705

Gnomad AMR exome AF: 0.0717

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.0349

Gnomad FIN exome AF: 0.0869

Gnomad NFE exome AF: 0.0647

Gnomad OTH exome AF: 0.0518

GnomAD4 exome AF: 0.0631 AC: 92103 AN: 1459728 Hom.: 3131 Cov.: 31 AF XY: 0.0623 AC XY: 45265 AN XY: 726222

African (AFR) AF: 0.0722 AC: 2414 AN: 33452

American (AMR) AF: 0.0690 AC: 3085 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0188 AC: 492 AN: 26132

East Asian (EAS) AF: 0.0319 AC: 1265 AN: 39694

South Asian (SAS) AF: 0.0533 AC: 4595 AN: 86176

European-Finnish (FIN) AF: 0.0829 AC: 4391 AN: 52968

Middle Eastern (MID) AF: 0.0290 AC: 152 AN: 5234

European-Non Finnish (NFE) AF: 0.0649 AC: 72080 AN: 1111098

Other (OTH) AF: 0.0602 AC: 3629 AN: 60290

GnomAD4 genome AF: 0.0669 AC: 10176 AN: 152048 Hom.: 358 Cov.: 31 AF XY: 0.0678 AC XY: 5039 AN XY: 74316

African (AFR) AF: 0.0705 AC: 2925 AN: 41462

American (AMR) AF: 0.0754 AC: 1151 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3470

East Asian (EAS) AF: 0.0366 AC: 189 AN: 5170

South Asian (SAS) AF: 0.0537 AC: 259 AN: 4822

European-Finnish (FIN) AF: 0.0867 AC: 916 AN: 10560

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

European-Non Finnish (NFE) AF: 0.0656 AC: 4459 AN: 67974

Other (OTH) AF: 0.0591 AC: 125 AN: 2114

Alfa AF: 0.0463 Hom.: 74

Bravo AF: 0.0668

Asia WGS AF: 0.0570 AC: 199 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Fanconi anemia complementation group P (4)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.19
DANN	Benign	0.58
PhyloP100		-0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80116508; hg19: chr16-3650970; COSMIC: COSV53561020;