rs76350200

Variant names:

• chr16-3597786-A-G
• rs76350200
• NM_032444.4:c.1366+11T>C

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.1366+11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0681 in 1,613,988 control chromosomes in the GnomAD database, including 4,100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (603 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3497 hom.)
• Consequence: SLX4 NM_032444.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0620
• Publications: 9 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=-0.92).
• BP6: Variant 16-3597786-A-G is Benign according to our data. Variant chr16-3597786-A-G is described in ClinVar as Benign. ClinVar VariationId is 262034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 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.1366+11T>C		intron	N/A	NP_115820.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	ENST00000294008.4	TSL:5 MANE Select	c.1366+11T>C		intron	N/A	ENSP00000294008.3
	SLX4	ENST00000466154.5	TSL:1	n.2587+11T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0840 AC: 12775 AN: 152062 Hom.: 600 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0833

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.0364

Gnomad SAS AF: 0.0572

Gnomad FIN AF: 0.0869

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0675

Gnomad OTH AF: 0.0766

GnomAD2 exomes AF: 0.0685 AC: 17147 AN: 250472 AF XY: 0.0657

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.0782

Gnomad ASJ exome AF: 0.0207

Gnomad EAS exome AF: 0.0350

Gnomad FIN exome AF: 0.0880

Gnomad NFE exome AF: 0.0674

Gnomad OTH exome AF: 0.0572

GnomAD4 exome AF: 0.0665 AC: 97141 AN: 1461808 Hom.: 3497 Cov.: 33 AF XY: 0.0656 AC XY: 47700 AN XY: 727208

African (AFR) AF: 0.124 AC: 4162 AN: 33480

American (AMR) AF: 0.0754 AC: 3372 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 527 AN: 26134

East Asian (EAS) AF: 0.0315 AC: 1252 AN: 39700

South Asian (SAS) AF: 0.0569 AC: 4905 AN: 86252

European-Finnish (FIN) AF: 0.0832 AC: 4439 AN: 53380

Middle Eastern (MID) AF: 0.0452 AC: 261 AN: 5768

European-Non Finnish (NFE) AF: 0.0667 AC: 74212 AN: 1111980

Other (OTH) AF: 0.0664 AC: 4011 AN: 60392

GnomAD4 genome AF: 0.0841 AC: 12795 AN: 152180 Hom.: 603 Cov.: 32 AF XY: 0.0844 AC XY: 6278 AN XY: 74412

African (AFR) AF: 0.126 AC: 5226 AN: 41494

American (AMR) AF: 0.0830 AC: 1269 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3472

East Asian (EAS) AF: 0.0363 AC: 188 AN: 5174

South Asian (SAS) AF: 0.0578 AC: 279 AN: 4824

European-Finnish (FIN) AF: 0.0869 AC: 922 AN: 10604

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0675 AC: 4592 AN: 68006

Other (OTH) AF: 0.0758 AC: 160 AN: 2110

Alfa AF: 0.0723 Hom.: 75

Bravo AF: 0.0862

Asia WGS AF: 0.0590 AC: 208 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fanconi anemia complementation group P (3)
-	-	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	-0.92
CADD	Benign	7.4
DANN	Benign	0.29
PhyloP100		0.062
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs76350200; hg19: chr16-3647787; COSMIC: COSV53561016; COSMIC: COSV53561016;