NM_032444.4:c.1706C>A

Variant names:

• chr16-3596371-G-T
• rs534528576
• NM_032444.4:c.1706C>A

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.1706C>A​(p.Pro569Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P569L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.937
• 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

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 (MetaRNN=0.04689634).

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.1706C>A	p.Pro569Gln	missense	Exon 8 of 15	NP_115820.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	ENST00000294008.4	TSL:5 MANE Select	c.1706C>A	p.Pro569Gln	missense	Exon 8 of 15	ENSP00000294008.3
	SLX4	ENST00000466154.5	TSL:1	n.2927C>A		non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444532 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 716312

⚠️ 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: 33238

American (AMR) AF: 0.00 AC: 0 AN: 43154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25656

East Asian (EAS) AF: 0.00 AC: 0 AN: 39162

South Asian (SAS) AF: 0.00 AC: 0 AN: 84644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102806

Other (OTH) AF: 0.00 AC: 0 AN: 59560

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.023
DANN	Benign	0.57
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.94
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.0080
Sift	Benign	0.36	T
Sift4G	Benign	0.37	T
Polyphen		0.011	B
Vest4		0.14
MutPred		0.34		Loss of catalytic residue at P569 (P = 0.0215)
MVP		0.030
MPC		0.068
ClinPred		0.073	T
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs534528576; hg19: chr16-3646372;