NM_032444.4:c.3677G>C

Variant names:

• chr16-3589961-C-G
• rs748607152
• NM_032444.4:c.3677G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032444.4(SLX4):​c.3677G>C​(p.Arg1226Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 151,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000026 (0 hom., cov: 32)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.28

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045913577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4	c.3677G>C	p.Arg1226Pro	missense_variant	Exon 12 of 15	ENST00000294008.4	NP_115820.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4	c.3677G>C	p.Arg1226Pro	missense_variant	Exon 12 of 15	5	NM_032444.4	ENSP00000294008.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151912 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74168

Gnomad4 AFR AF: 0.0000968

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia complementation group P Uncertain:1

Jan 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.0060
DANN	Benign	0.69
DEOGEN2	Benign	0.042	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.024
Sift	Benign	0.13	T
Sift4G	Benign	0.28	T
Polyphen		0.0090	B
Vest4		0.12
MutPred		0.17		Gain of relative solvent accessibility (P = 0.0249);
MVP		0.061
MPC		0.076
ClinPred		0.12	T
GERP RS		-8.7
Varity_R		0.18
gMVP		0.16

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

Publications

LitVar

Other links and lift over

dbSNP: rs748607152; hg19: chr16-3639962;