rs116840807

Variant names:

• chr3-197951224-CTCT-C
• rs116840807
• NM_000996.4:c.82_84delCTT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_000996.4(RPL35A):​c.82_84delCTT​(p.Leu28del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPL35A NM_000996.4 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 7.64

Genes affected

RPL35A (HGNC:10345): (ribosomal protein L35a) 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 60S subunit. The protein belongs to the L35AE family of ribosomal proteins. It is located in the cytoplasm. The rat protein has been shown to bind to both initiator and elongator tRNAs, and thus, it is located at the P site, or P and A sites, of the ribosome. Although this gene was originally mapped to chromosome 18, it has been established that it is located at 3q29-qter. Alternative splicing results in multiple transcript variants. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Oct 2015]

IQCG (HGNC:25251): (IQ motif containing G) Enables Hsp70 protein binding activity and calmodulin binding activity. Predicted to be involved in sperm axoneme assembly. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000996.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 3-197951224-CTCT-C is Pathogenic according to our data. Variant chr3-197951224-CTCT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13002.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL35A	NM_000996.4	c.82_84delCTT	p.Leu28del	conservative_inframe_deletion	Exon 3 of 5	ENST00000647248.2	NP_000987.2
IQCG	NM_032263.5	c.-59-5541_-59-5539delAGA		intron_variant	Intron 2 of 11	ENST00000265239.11	NP_115639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL35A	ENST00000647248.2	c.82_84delCTT	p.Leu28del	conservative_inframe_deletion	Exon 3 of 5		NM_000996.4	ENSP00000495672.1
IQCG	ENST00000265239.11	c.-59-5541_-59-5539delAGA		intron_variant	Intron 2 of 11	1	NM_032263.5	ENSP00000265239.6

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Diamond-Blackfan anemia 5 Pathogenic:2 Uncertain:1

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.82_84del, results in the deletion of 1 amino acid(s) of the RPL35A protein (p.Leu28del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of Diamond-Blackfan anemia (PMID: 18535205, 28102861, 33718801, 37376976). This variant is also known as c.78_80delTCT. ClinVar contains an entry for this variant (Variation ID: 13002). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sep 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RPL35A: PP4:Strong, PM2, PM4, PS4:Moderate, PP1 -

Nov 10, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.82_84delCTT variant has been published as a pathogenic variant in one individual with Diamond-Blackfan anemia (Farrar et al., 2008). The variant is not observed in large population cohorts (Lek et al., 2016). The c.82_84delCTT variant causes an in-frame deletion of Leucine 28. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs116840807; hg19: chr3-197678095;