19-41865745-G-C

Variant names:

• chr19-41865745-G-C
• rs61761238
• NM_001022.4:c.173-3286G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001022.4(RPS19):​c.173-3286G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 151,602 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.011 (17 hom., cov: 29)
• Consequence: RPS19 NM_001022.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.232
• Publications: 1 publications found

Genes affected

RPS19 (HGNC:10402): (ribosomal protein S19) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S19E family of ribosomal proteins. It is located in the cytoplasm. Mutations in this gene cause Diamond-Blackfan anemia (DBA), a constitutional erythroblastopenia characterized by absent or decreased erythroid precursors, in a subset of patients. This suggests a possible extra-ribosomal function for this gene in erythropoietic differentiation and proliferation, in addition to its ribosomal function. Higher expression levels of this gene in some primary colon carcinomas compared to matched normal colon tissues has been observed. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

RPS19 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Diamond-Blackfan anemia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0113 (1720/151602) while in subpopulation NFE AF = 0.0168 (1138/67912). AF 95% confidence interval is 0.0159. There are 17 homozygotes in GnomAd4. There are 818 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1720 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS19	NM_001022.4	c.173-3286G>C		intron_variant	Intron 3 of 5	ENST00000598742.6	NP_001013.1
RPS19	NM_001321485.2	c.186-3286G>C		intron_variant	Intron 3 of 5		NP_001308414.1
RPS19	NM_001321483.2	c.173-3286G>C		intron_variant	Intron 3 of 5		NP_001308412.1
RPS19	NM_001321484.2	c.173-3286G>C		intron_variant	Intron 3 of 5		NP_001308413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS19	ENST00000598742.6	c.173-3286G>C		intron_variant	Intron 3 of 5	1	NM_001022.4	ENSP00000470972.1

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1721 AN: 151486 Hom.: 17 Cov.: 29

Gnomad AFR AF: 0.00330

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00349

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00398

Gnomad FIN AF: 0.0260

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.00818

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0113 AC: 1720 AN: 151602 Hom.: 17 Cov.: 29 AF XY: 0.0110 AC XY: 818 AN XY: 74028

African (AFR) AF: 0.00329 AC: 136 AN: 41304

American (AMR) AF: 0.00348 AC: 53 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3466

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5132

South Asian (SAS) AF: 0.00377 AC: 18 AN: 4774

European-Finnish (FIN) AF: 0.0260 AC: 273 AN: 10492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0168 AC: 1138 AN: 67912

Other (OTH) AF: 0.00810 AC: 17 AN: 2100

Alfa AF: 0.00532 Hom.: 2

Bravo AF: 0.00900

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.9
DANN	Benign	0.80
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism

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: rs61761238; hg19: chr19-42369814;