NM_001022.4:c.72-92A>G

Variant names:

• chr19-41861020-A-G
• rs566047445
• NM_001022.4:c.72-92A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001022.4(RPS19):​c.72-92A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,138,532 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (7 hom.)
• Consequence: RPS19 NM_001022.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.649
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-41861020-A-G is Benign according to our data. Variant chr19-41861020-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 238215.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 222 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS19	NM_001022.4	MANE Select	c.72-92A>G		intron	N/A	NP_001013.1
	RPS19	NM_001321485.2		c.72-92A>G		intron	N/A	NP_001308414.1
	RPS19	NM_001321483.2		c.72-92A>G		intron	N/A	NP_001308412.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS19	ENST00000598742.6	TSL:1 MANE Select	c.72-92A>G		intron	N/A	ENSP00000470972.1
	RPS19	ENST00000593863.5	TSL:3	c.72-92A>G		intron	N/A	ENSP00000470004.1
	RPS19	ENST00000600467.6	TSL:2	c.72-92A>G		intron	N/A	ENSP00000469228.2

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 222 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00247

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.00183 AC: 1807 AN: 986202 Hom.: 7 Cov.: 13 AF XY: 0.00175 AC XY: 896 AN XY: 511264

African (AFR) AF: 0.000332 AC: 8 AN: 24112

American (AMR) AF: 0.00159 AC: 68 AN: 42662

Ashkenazi Jewish (ASJ) AF: 0.0000431 AC: 1 AN: 23192

East Asian (EAS) AF: 0.00 AC: 0 AN: 37388

South Asian (SAS) AF: 0.00 AC: 0 AN: 76272

European-Finnish (FIN) AF: 0.000386 AC: 20 AN: 51750

Middle Eastern (MID) AF: 0.000863 AC: 3 AN: 3478

European-Non Finnish (NFE) AF: 0.00239 AC: 1629 AN: 682764

Other (OTH) AF: 0.00175 AC: 78 AN: 44584

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74494

African (AFR) AF: 0.000409 AC: 17 AN: 41588

American (AMR) AF: 0.00183 AC: 28 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00247 AC: 168 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00191 Hom.: 0

Bravo AF: 0.00162

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia Benign:1

Jan 18, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.7
DANN	Benign	0.32
PhyloP100		-0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs566047445; hg19: chr19-42365089;