rs772862460

Variant names:

• chr3-197950934-A-G
• rs772862460
• NM_032263.5:c.-59-5248T>C

Your query was ambiguous. Multiple possible variants found:

• chr3-197950934-A-G
• chr3-197950934-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000996.4(RPL35A):​c.-32-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPL35A NM_000996.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.79

Genes affected

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 12, offset of -1, new splice context is: aatctttttgtttgttttAGggc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQCG	NM_032263.5	c.-59-5248T>C		intron_variant	Intron 2 of 11	ENST00000265239.11	NP_115639.1
RPL35A	NM_000996.4	c.-32-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 4	ENST00000647248.2	NP_000987.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQCG	ENST00000265239.11	c.-59-5248T>C		intron_variant	Intron 2 of 11	1	NM_032263.5	ENSP00000265239.6
RPL35A	ENST00000647248.2	c.-32-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 4		NM_000996.4	ENSP00000495672.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	35
DANN	Uncertain	0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 1
DS_AL_spliceai		1.0		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs772862460; hg19: chr3-197677805;