16-30197073-C-T

Variant names:

• chr16-30197073-C-T
• NM_001014999.3:c.682C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001014999.3(SLX1A):​c.682C>T​(p.Leu228Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 16)
• Consequence: SLX1A NM_001014999.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.22

Genes affected

SLX1A (HGNC:20922): (SLX1 homolog A, 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 centromeric copy. Alternative splicing results in multiple transcript variants. Read-through transcription also occurs between this gene and the downstream SULT1A3 (sulfotransferase family, cytosolic, 1A, phenol-preferring, member 3) gene. [provided by RefSeq, Nov 2010]

SLX1A-SULT1A3 (HGNC:44437): (SLX1A-SULT1A3 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring SLX1A (SLX1 structure-specific endonuclease subunit homolog A) and SULT1A3 (sulfotransferase family, cytosolic, 1A, phenol-preferring, member 3) genes on the short arm of chromosome 16. A duplicate read-through locus also exists between the SLX1B and SULT1A4 genes located approximately 730 kb upstream 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21309069).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX1A	NM_001014999.3	c.682C>T	p.Leu228Phe	missense_variant	Exon 4 of 6	ENST00000251303.11	NP_001014999.1
SLX1A	NM_001015000.2	c.340C>T	p.Leu114Phe	missense_variant	Exon 3 of 5		NP_001015000.1
SLX1A-SULT1A3	NR_037608.1	n.801C>T		non_coding_transcript_exon_variant	Exon 3 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLX1A	ENST00000251303.11	c.682C>T	p.Leu228Phe	missense_variant	Exon 4 of 6	1	NM_001014999.3	ENSP00000251303.7

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome Cov.: 21

GnomAD4 genome Cov.: 16

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.682C>T (p.L228F) alteration is located in exon 4 (coding exon 4) of the SLX1A gene. This alteration results from a C to T substitution at nucleotide position 682, causing the leucine (L) at amino acid position 228 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
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	.;T
Eigen	Benign	0.085
Eigen_PC	Benign	0.078
FATHMM_MKL	Benign	0.75	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.8	.;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.27
Sift	Benign	0.52	T;T
Sift4G	Benign	0.13	T;T
Vest4		0.34
MutPred		0.46		.;Gain of helix (P = 0.0349);
MVP		0.082
MPC		3.4
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.18
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-30208394;