16-29457930-G-T

Variant names:

• chr16-29457930-G-T
• rs921332009
• ENST00000330181.10:c.713G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_024044.5(SLX1B):​c.713G>T​(p.Cys238Phe) variant causes a missense, splice region change. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000076 (0 hom., cov: 18)
  • Failed GnomAD Quality Control
• Consequence: SLX1B NM_024044.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.23

Genes affected

SLX1B (HGNC:28748): (SLX1 homolog B, structure-specific endonuclease subunit) This gene encodes a protein that is an important regulator of genome stability. The protein represents the catalytic subunit of the SLX1-SLX4 structure-specific endonuclease, which can resolve DNA secondary structures that are formed during repair and recombination processes. Two identical copies of this gene are located on the p arm of chromosome 16 due to a segmental duplication; this record represents the more telomeric copy. Alternative splicing results in multiple transcript variants. Read-through transcription also occurs between this gene and the downstream SULT1A4 (sulfotransferase family, cytosolic, 1A, phenol-preferring, member 4) gene. [provided by RefSeq, Nov 2010]

SLX1B-SULT1A4 (HGNC:48353): (SLX1B-SULT1A4 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring SLX1B (SLX1 structure-specific endonuclease subunit homolog B) and SULT1A4 (sulfotransferase family, cytosolic, 1A, phenol-preferring, member 4) genes on the short arm of chromosome 16. A duplicate read-through locus also exists between the SLX1A and SULT1A3 genes located approximately 730 kb downstream on the same chromosome. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2017]

ENSG00000288632 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX1B	NM_024044.5	c.713G>T	p.Cys238Phe	missense_variant, splice_region_variant	Exon 5 of 6		NP_076949.1
SLX1B	NM_001400286.1	c.707G>T	p.Cys236Phe	missense_variant, splice_region_variant	Exon 5 of 6		NP_001387215.1
SLX1B	NM_178044.4	c.371G>T	p.Cys124Phe	missense_variant, splice_region_variant	Exon 4 of 5		NP_835145.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLX1B	ENST00000330181.10	c.713G>T	p.Cys238Phe	missense_variant, splice_region_variant	Exon 5 of 6	1		ENSP00000328940.5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 130880 Hom.: 0 Cov.: 18 FAILED QC

Gnomad AFR AF: 0.0000252

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.: 14

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000764 AC: 1 AN: 130880 Hom.: 0 Cov.: 18 AF XY: 0.0000159 AC XY: 1 AN XY: 62898

Gnomad4 AFR AF: 0.0000252

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: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.713G>T (p.C238F) alteration is located in exon 5 (coding exon 5) of the SLX1B gene. This alteration results from a G to T substitution at nucleotide position 713, causing the cysteine (C) at amino acid position 238 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	0.98
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.021	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-10	D;D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.83
MutPred		0.83		Loss of loop (P = 0.0804);.;
MVP		0.24
MPC		4.9
ClinPred		1.0	D
GERP RS		2.5
gMVP		0.83

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: rs921332009; hg19: chr16-29469251;