NM_001014999.3:c.317C>G

Variant names:

• chr16-30194962-C-G
• rs1440893408
• NM_001014999.3:c.317C>G

Variant summary

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

The NM_001014999.3(SLX1A):​c.317C>G​(p.Ala106Gly) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A106V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 21)
  • Failed GnomAD Quality Control
• Consequence: SLX1A NM_001014999.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.02
• Publications: 0 publications found

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

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=0.124513835).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001014999.3. 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
	SLX1A	NM_001014999.3	MANE Select	c.317C>G	p.Ala106Gly	missense	Exon 3 of 6	NP_001014999.1	Q9BQ83-1
	SLX1A	NM_001015000.2		c.240+171C>G		intron	N/A	NP_001015000.1	Q9BQ83-2
	SLX1A-SULT1A3	NR_037608.1		n.436C>G		non_coding_transcript_exon	Exon 2 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX1A	ENST00000251303.11	TSL:1 MANE Select	c.317C>G	p.Ala106Gly	missense	Exon 3 of 6	ENSP00000251303.7	Q9BQ83-1
	SLX1A	ENST00000345535.9	TSL:1	c.240+171C>G		intron	N/A	ENSP00000333945.4	Q9BQ83-2
	SLX1A	ENST00000941762.1		c.374C>G	p.Ala125Gly	missense	Exon 3 of 6	ENSP00000611821.1

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150632 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000243

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.: 23

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000664 AC: 1 AN: 150632 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 73462

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000243 AC: 1 AN: 41144

American (AMR) AF: 0.00 AC: 0 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 4876

South Asian (SAS) AF: 0.00 AC: 0 AN: 4734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67448

Other (OTH) AF: 0.00 AC: 0 AN: 2068

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	20
DANN	Benign	0.72
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.50	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.056
Sift	Benign	0.40	T
Sift4G	Benign	0.44	T
Vest4		0.085
MutPred		0.36		Loss of helix (P = 0.0237)
MVP		0.068
MPC		1.8
ClinPred		0.11	T
GERP RS		2.9
Varity_R		0.082
gMVP		0.38

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: rs1440893408; hg19: chr16-30206283;