3-197950221-G-A

Position:

• chr3-197950221-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000265239.11(IQCG):​c.-59-4535C>T variant causes a intron change. The variant allele was found at a frequency of 0.00215 in 1,231,352 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (3 hom.)
• Consequence: IQCG ENST00000265239.11 intron
• Scores: Splicing: ADA: 0.6300
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.63

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPL35A	NM_000996.4	c.-33G>A		splice_region_variant, 5_prime_UTR_variant	1/5	ENST00000647248.2	NP_000987.2
IQCG	NM_032263.5	c.-59-4535C>T		intron_variant		ENST00000265239.11	NP_115639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPL35A	ENST00000647248.2	c.-33G>A		splice_region_variant, 5_prime_UTR_variant	1/5		NM_000996.4	ENSP00000495672	P1
IQCG	ENST00000265239.11	c.-59-4535C>T		intron_variant		1	NM_032263.5	ENSP00000265239	P1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152256 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00227 AC: 2446 AN: 1078978 Hom.: 3 Cov.: 30 AF XY: 0.00232 AC XY: 1182 AN XY: 509334

Gnomad4 AFR exome AF: 0.000610

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.000834

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00296

Gnomad4 FIN exome AF: 0.00104

Gnomad4 NFE exome AF: 0.00245

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152374 Hom.: 0 Cov.: 33 AF XY: 0.00154 AC XY: 115 AN XY: 74504

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00210

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000742 Hom.: 0

Bravo AF: 0.00135

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	24
DANN	Benign	0.84
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.63
dbscSNV1_RF	Benign	0.47
SpliceAI score (max)		0.16		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: rs564722971; hg19: chr3-197677092;