19-41864668-G-A

Variant names:

• chr19-41864668-G-A
• rs7254214
• NM_001022.4:c.172+3456G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001022.4(RPS19):​c.172+3456G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.415 in 152,140 control chromosomes in the GnomAD database, including 15,200 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 0.42 (15190 hom., cov: 31)
  • Exomes 𝑓: 0.41 (10 hom.)
• Consequence: RPS19 NM_001022.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.54
• Publications: 20 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=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001022.4. 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
	RPS19	NM_001022.4	MANE Select	c.172+3456G>A		intron	N/A	NP_001013.1
	RPS19	NM_001321485.2		c.185+3443G>A		intron	N/A	NP_001308414.1
	RPS19	NM_001321483.2		c.172+3456G>A		intron	N/A	NP_001308412.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS19	ENST00000598742.6	TSL:1 MANE Select	c.172+3456G>A		intron	N/A	ENSP00000470972.1
	RPS19	ENST00000593863.5	TSL:3	c.172+3456G>A		intron	N/A	ENSP00000470004.1
	RPS19	ENST00000600467.6	TSL:2	c.172+3456G>A		intron	N/A	ENSP00000469228.2

Frequencies

GnomAD3 genomes AF: 0.415 AC: 63089 AN: 151902 Hom.: 15193 Cov.: 31

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.563

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.573

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.678

Gnomad NFE AF: 0.513

Gnomad OTH AF: 0.475

GnomAD4 exome AF: 0.408 AC: 49 AN: 120 Hom.: 10 Cov.: 0 AF XY: 0.330 AC XY: 29 AN XY: 88

African (AFR) AF: 0.167 AC: 1 AN: 6

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.333 AC: 2 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.398 AC: 39 AN: 98

Other (OTH) AF: 0.750 AC: 6 AN: 8

GnomAD4 genome AF: 0.415 AC: 63089 AN: 152020 Hom.: 15190 Cov.: 31 AF XY: 0.420 AC XY: 31228 AN XY: 74308

African (AFR) AF: 0.153 AC: 6353 AN: 41488

American (AMR) AF: 0.490 AC: 7481 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2132 AN: 3470

East Asian (EAS) AF: 0.460 AC: 2375 AN: 5164

South Asian (SAS) AF: 0.572 AC: 2753 AN: 4816

European-Finnish (FIN) AF: 0.516 AC: 5454 AN: 10568

Middle Eastern (MID) AF: 0.678 AC: 198 AN: 292

European-Non Finnish (NFE) AF: 0.513 AC: 34840 AN: 67934

Other (OTH) AF: 0.470 AC: 992 AN: 2112

Alfa AF: 0.497 Hom.: 35641

Bravo AF: 0.398

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.23
PhyloP100		-2.5

Splicing

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

Other links and lift over

dbSNP: rs7254214; hg19: chr19-42368738;