chr1-92833391-G-A

Variant names:

• chr1-92833391-G-A
• rs769877057
• NM_000969.5:c.6G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_000969.5(RPL5):​c.6G>A​(p.Gly2Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RPL5 NM_000969.5 splice_region, synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.31
• Publications: 0 publications found

Genes affected

RPL5 (HGNC:10360): (ribosomal protein L5) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of four RNA species and approximately 80 structurally distinct proteins. This gene encodes a member of the L18P family of ribosomal proteins and component of the 60S subunit. The encoded protein binds 5S rRNA to form a stable complex called the 5S ribonucleoprotein particle (RNP), which is necessary for the transport of nonribosome-associated cytoplasmic 5S rRNA to the nucleolus for assembly into ribosomes. The encoded protein may also function to inhibit tumorigenesis through the activation of downstream tumor suppressors and the downregulation of oncoprotein expression. Mutations in this gene have been identified in patients with Diamond-Blackfan Anemia (DBA). This gene is co-transcribed with the small nucleolar RNA gene U21, which is located in its fifth intron. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed throughout the genome. [provided by RefSeq, Mar 2017]

DIPK1A (HGNC:32213): (divergent protein kinase domain 1A) This gene encodes a member of the FAM69 family of cysteine-rich type II transmembrane proteins. These proteins localize to the endoplasmic reticulum but their specific functions are unknown. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 1-92833391-G-A is Benign according to our data. Variant chr1-92833391-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2995719.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.31 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000969.5. 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
	RPL5	NM_000969.5	MANE Select	c.6G>A	p.Gly2Gly	splice_region synonymous	Exon 2 of 8	NP_000960.2
	DIPK1A	NM_001252273.2		c.475-357C>T		intron	N/A	NP_001239202.1	Q5T7M9-2
	RPL5	NR_146333.1		n.135G>A		splice_region non_coding_transcript_exon	Exon 2 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL5	ENST00000370321.8	TSL:1 MANE Select	c.6G>A	p.Gly2Gly	splice_region synonymous	Exon 2 of 8	ENSP00000359345.2	P46777
	DIPK1A	ENST00000615519.4	TSL:1	c.475-357C>T		intron	N/A	ENSP00000483279.1	Q5T7M9-2
	RPL5	ENST00000315741.5	TSL:5	c.-145G>A		splice_region	Exon 2 of 6	ENSP00000359338.2	Q5T7N0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250620 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458116 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725684

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108748

Other (OTH) AF: 0.00 AC: 0 AN: 60250

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Diamond-Blackfan anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.91
PhyloP100		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=89/11	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: rs769877057; hg19: chr1-93298948;