16-3581301-T-C

Variant names:

• chr16-3581301-T-C
• rs117958592
• NM_032444.4:c.*1041A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_032444.4(SLX4):​c.*1041A>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 0.00289 in 152,858 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (0 hom.)
• Consequence: SLX4 NM_032444.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.581
• Publications: 1 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-3581301-T-C is Benign according to our data. Variant chr16-3581301-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 888239.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00289 (441/152356) while in subpopulation NFE AF = 0.005 (340/68028). AF 95% confidence interval is 0.00456. There are 1 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4	c.*1041A>G		3_prime_UTR_variant	Exon 15 of 15	ENST00000294008.4	NP_115820.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4	c.*1041A>G		3_prime_UTR_variant	Exon 15 of 15	5	NM_032444.4	ENSP00000294008.3
ENSG00000261938	ENST00000573982.1	n.121T>C		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 441 AN: 152238 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00500

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00199 AC: 1 AN: 502 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 304

⚠️ 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: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00230 AC: 1 AN: 434

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52

Other (OTH) AF: 0.00 AC: 0 AN: 14

⚠️ 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 AF: 0.00289 AC: 441 AN: 152356 Hom.: 1 Cov.: 33 AF XY: 0.00263 AC XY: 196 AN XY: 74510

African (AFR) AF: 0.000577 AC: 24 AN: 41586

American (AMR) AF: 0.000980 AC: 15 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00500 AC: 340 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00500 Hom.: 0

Bravo AF: 0.00276

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia complementation group P Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.1
DANN	Benign	0.37
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism

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: rs117958592; hg19: chr16-3631302;