16-3589267-C-G

Variant names:

• chr16-3589267-C-G
• rs745485209
• NM_032444.4:c.4371G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032444.4(SLX4):​c.4371G>C​(p.Arg1457Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,448,718 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R1457R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.855
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10218999).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	NM_032444.4	MANE Select	c.4371G>C	p.Arg1457Ser	missense	Exon 12 of 15	NP_115820.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	ENST00000294008.4	TSL:5 MANE Select	c.4371G>C	p.Arg1457Ser	missense	Exon 12 of 15	ENSP00000294008.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1448718 Hom.: 0 Cov.: 38 AF XY: 0.00000417 AC XY: 3 AN XY: 718794

African (AFR) AF: 0.00 AC: 0 AN: 33084

American (AMR) AF: 0.00 AC: 0 AN: 43856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25366

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 84458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00000453 AC: 5 AN: 1104054

Other (OTH) AF: 0.00 AC: 0 AN: 59778

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.85
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.10
Sift	Benign	0.074	T
Sift4G	Benign	0.36	T
Polyphen		0.49	P
Vest4		0.13
MutPred		0.18		Gain of phosphorylation at R1457 (P = 0.0146)
MVP		0.26
MPC		0.072
ClinPred		0.14	T
GERP RS		3.3
Varity_R		0.15
gMVP		0.13
Mutation Taster		=89/11	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: rs745485209; hg19: chr16-3639268;