rs75146816

Variant names:

• chr16-3581621-A-G
• rs75146816
• NM_032444.4:c.*721T>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.*721T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0499 in 153,480 control chromosomes in the GnomAD database, including 244 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (243 hom., cov: 33)
  • Exomes 𝑓: 0.052 (1 hom.)
• Consequence: SLX4 NM_032444.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.47
• Publications: 5 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• 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

ENSG00000261938 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 16-3581621-A-G is Benign according to our data. Variant chr16-3581621-A-G is described in ClinVar as Benign. ClinVar VariationId is 319130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0645 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.*721T>C		3_prime_UTR	Exon 15 of 15	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.*721T>C		3_prime_UTR	Exon 15 of 15	ENSP00000294008.3	Q8IY92-1
	ENSG00000261938	ENST00000573982.1	TSL:3	n.198+243A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0500 AC: 7607 AN: 152208 Hom.: 243 Cov.: 33

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0682

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0364

Gnomad SAS AF: 0.0532

Gnomad FIN AF: 0.0866

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0654

Gnomad OTH AF: 0.0488

GnomAD4 exome AF: 0.0520 AC: 60 AN: 1154 Hom.: 1 Cov.: 0 AF XY: 0.0476 AC XY: 30 AN XY: 630

African (AFR) AF: 0.00 AC: 0 AN: 14

American (AMR) AF: 0.0370 AC: 4 AN: 108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 8

South Asian (SAS) AF: 0.00 AC: 0 AN: 24

European-Finnish (FIN) AF: 0.0766 AC: 19 AN: 248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.0490 AC: 35 AN: 714

Other (OTH) AF: 0.0625 AC: 2 AN: 32

GnomAD4 genome AF: 0.0499 AC: 7603 AN: 152326 Hom.: 243 Cov.: 33 AF XY: 0.0513 AC XY: 3824 AN XY: 74490

African (AFR) AF: 0.0119 AC: 494 AN: 41576

American (AMR) AF: 0.0679 AC: 1039 AN: 15302

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

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

South Asian (SAS) AF: 0.0540 AC: 261 AN: 4830

European-Finnish (FIN) AF: 0.0866 AC: 920 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0654 AC: 4448 AN: 68016

Other (OTH) AF: 0.0478 AC: 101 AN: 2114

Alfa AF: 0.0606 Hom.: 33

Bravo AF: 0.0466

Asia WGS AF: 0.0510 AC: 178 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.27
DANN	Benign	0.24
PhyloP100		-1.5
Mutation Taster		=99/1	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: rs75146816; hg19: chr16-3631622;