16-3581873-T-C

Variant names:

• chr16-3581873-T-C
• rs868278470
• NM_032444.4:c.*469A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032444.4(SLX4):​c.*469A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 40,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: SLX4 NM_032444.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 0 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

ENSG00000261938 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4	c.*469A>G		3_prime_UTR_variant	Exon 15 of 15	ENST00000294008.4	NP_115820.2
SLX4	XM_024450471.2	c.*469A>G		3_prime_UTR_variant	Exon 15 of 15		XP_024306239.1
SLX4	XM_011522715.4	c.*469A>G		3_prime_UTR_variant	Exon 15 of 15		XP_011521017.1
SLX4	XM_047434801.1	c.*469A>G		3_prime_UTR_variant	Exon 11 of 11		XP_047290757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4	c.*469A>G		3_prime_UTR_variant	Exon 15 of 15	5	NM_032444.4	ENSP00000294008.3
ENSG00000261938	ENST00000573982.1	n.198+495T>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000248 AC: 1 AN: 40396 Hom.: 0 Cov.: 0 AF XY: 0.0000493 AC XY: 1 AN XY: 20278

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 986

American (AMR) AF: 0.00 AC: 0 AN: 3406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1380

East Asian (EAS) AF: 0.00 AC: 0 AN: 5380

South Asian (SAS) AF: 0.00 AC: 0 AN: 3602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 146

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 22510

Other (OTH) AF: 0.000422 AC: 1 AN: 2372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.1
DANN	Benign	0.30
PhyloP100		-1.2

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: rs868278470; hg19: chr16-3631874;