rs140192228

Variant names:

• chr16-1945498-C-T
• rs140192228
• NM_005061.3:c.1167+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1945498-C-T
• chr16-1945498-C-A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PVS1_Moderate BP6 BS2

The NM_005061.3(RPL3L):​c.1167+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,610,416 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (9 hom.)
• Consequence: RPL3L NM_005061.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.91
• Publications: 9 publications found

Genes affected

RPL3L (HGNC:10351): (ribosomal protein L3 like) This gene encodes a protein that shares sequence similarity with ribosomal protein L3. The protein belongs to the L3P family of ribosomal proteins. Unlike the ubiquitous expression of ribosomal protein genes, this gene has a tissue-specific pattern of expression, with the highest levels of expression in skeletal muscle and heart. It is not currently known whether the encoded protein is a functional ribosomal protein or whether it has evolved a function that is independent of the ribosome. [provided by RefSeq, Jul 2008]

RPL3L Gene-Disease associations (from GenCC):

• cardiomyopathy, dilated, 2D

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.09803922 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BP6: Variant 16-1945498-C-T is Benign according to our data. Variant chr16-1945498-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2413034.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005061.3. 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
	RPL3L	NM_005061.3	MANE Select	c.1167+1G>A		splice_donor intron	N/A	NP_005052.1	Q92901

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL3L	ENST00000268661.8	TSL:1 MANE Select	c.1167+1G>A		splice_donor intron	N/A	ENSP00000268661.7	Q92901
	RPL3L	ENST00000968104.1		c.1242+1G>A		splice_donor intron	N/A	ENSP00000638163.1
	RPL3L	ENST00000968108.1		c.1227+1G>A		splice_donor intron	N/A	ENSP00000638167.1

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00118 AC: 289 AN: 244244 AF XY: 0.00124

Gnomad AFR exome AF: 0.000516

Gnomad AMR exome AF: 0.000819

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000551

Gnomad FIN exome AF: 0.000472

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00257 AC: 3746 AN: 1458142 Hom.: 9 Cov.: 32 AF XY: 0.00244 AC XY: 1772 AN XY: 725042

African (AFR) AF: 0.000329 AC: 11 AN: 33418

American (AMR) AF: 0.000877 AC: 39 AN: 44450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 85520

European-Finnish (FIN) AF: 0.000474 AC: 25 AN: 52756

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5706

European-Non Finnish (NFE) AF: 0.00316 AC: 3512 AN: 1110382

Other (OTH) AF: 0.00261 AC: 157 AN: 60250

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74450

African (AFR) AF: 0.000650 AC: 27 AN: 41566

American (AMR) AF: 0.000915 AC: 14 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00285 AC: 194 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00182 Hom.: 2

Bravo AF: 0.00161

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.000915 AC: 111

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.9
GERP RS		3.9
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs140192228; hg19: chr16-1995499;