rs749576571

Variant names:

• chr16-11841819-T-C
• rs749576571
• NM_015659.3:c.731A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The ENST00000355674.9(RSL1D1):​c.730-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000548 in 1,460,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: RSL1D1 ENST00000355674.9 splice_acceptor, intron
• Scores: Splicing: ADA: 0.1606
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80
• Publications: 0 publications found

Genes affected

RSL1D1 (HGNC:24534): (ribosomal L1 domain containing 1) Enables mRNA 3'-UTR binding activity and mRNA 5'-UTR binding activity. Involved in regulation of apoptotic process and regulation of cellular senescence. Acts upstream of or within regulation of protein localization. Located in chromosome and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.09527498 fraction of the gene. Cryptic splice site detected, with MaxEntScore 2.1, offset of -1, new splice context is: ctcttttctttgtttcagAGgtg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000355674.9. 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
	RSL1D1	NM_015659.3	MANE Select	c.731A>G	p.Lys244Arg	missense splice_region	Exon 7 of 9	NP_056474.2	O76021-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSL1D1	ENST00000571133.6	TSL:1 MANE Select	c.731A>G	p.Lys244Arg	missense splice_region	Exon 7 of 9	ENSP00000460871.1	O76021-1
	RSL1D1	ENST00000355674.9	TSL:1	c.730-2A>G		splice_acceptor intron	N/A	ENSP00000347897.5	J3QSV6
	RSL1D1	ENST00000898748.1		c.758A>G	p.Lys253Arg	missense	Exon 7 of 9	ENSP00000568807.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249550 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460692 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726588

African (AFR) AF: 0.00 AC: 0 AN: 33392

American (AMR) AF: 0.00 AC: 0 AN: 44412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 85842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111738

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	0.11
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Uncertain	0.13	D
PhyloP100		5.8
ClinPred		0.96	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.16
dbscSNV1_RF	Benign	0.45
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -1

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

Other links and lift over

dbSNP: rs749576571; hg19: chr16-11935676;