chr3-197951224-CTCT-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 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
• Publications: 4 publications found

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]

DRC9 (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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000996.4
• 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 VariationId is 13002.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000996.4. 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
	RPL35A	NM_000996.4	MANE Select	c.82_84delCTT	p.Leu28del	conservative_inframe_deletion	Exon 3 of 5	NP_000987.2
	DRC9	NM_032263.5	MANE Select	c.-59-5541_-59-5539delAGA		intron	N/A	NP_115639.1	Q9H095-1
	RPL35A	NM_001316311.2		c.82_84delCTT	p.Leu28del	conservative_inframe_deletion	Exon 3 of 5	NP_001303240.1	P18077

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL35A	ENST00000647248.2	MANE Select	c.82_84delCTT	p.Leu28del	conservative_inframe_deletion	Exon 3 of 5	ENSP00000495672.1	P18077
	RPL35A	ENST00000448864.6	TSL:1	c.82_84delCTT	p.Leu28del	conservative_inframe_deletion	Exon 3 of 5	ENSP00000393393.1	P18077
	IQCG	ENST00000265239.11	TSL:1 MANE Select	c.-59-5541_-59-5539delAGA		intron	N/A	ENSP00000265239.6	Q9H095-1

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Diamond-Blackfan anemia 5 (3)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=42/58	disease causing

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: rs116840807; hg19: chr3-197678095;