NM_000996.4:c.-33G>A

Variant names:

• chr3-197950221-G-A
• rs564722971
• NM_000996.4:c.-33G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000996.4(RPL35A):​c.-33G>A variant causes a splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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: RPL35A NM_000996.4 splice_region
• Scores: Splicing: ADA: 0.6300
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.63
• Publications: 0 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BS2: High AC in GnomAd4 at 206 AD gene.

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.-33G>A		splice_region	Exon 1 of 5	NP_000987.2
	RPL35A	NM_000996.4	MANE Select	c.-33G>A		5_prime_UTR	Exon 1 of 5	NP_000987.2
	DRC9	NM_032263.5	MANE Select	c.-59-4535C>T		intron	N/A	NP_115639.1	Q9H095-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL35A	ENST00000647248.2	MANE Select	c.-33G>A		splice_region	Exon 1 of 5	ENSP00000495672.1	P18077
	RPL35A	ENST00000647248.2	MANE Select	c.-33G>A		5_prime_UTR	Exon 1 of 5	ENSP00000495672.1	P18077
	RPL35A	ENST00000448864.6	TSL:1	c.-111G>A		5_prime_UTR	Exon 1 of 5	ENSP00000393393.1	P18077

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

African (AFR) AF: 0.000610 AC: 14 AN: 22962

American (AMR) AF: 0.00143 AC: 12 AN: 8408

Ashkenazi Jewish (ASJ) AF: 0.000834 AC: 12 AN: 14386

East Asian (EAS) AF: 0.00 AC: 0 AN: 26508

South Asian (SAS) AF: 0.00296 AC: 57 AN: 19268

European-Finnish (FIN) AF: 0.00104 AC: 22 AN: 21054

Middle Eastern (MID) AF: 0.00275 AC: 8 AN: 2910

European-Non Finnish (NFE) AF: 0.00245 AC: 2253 AN: 919838

Other (OTH) AF: 0.00156 AC: 68 AN: 43644

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

African (AFR) AF: 0.000409 AC: 17 AN: 41590

American (AMR) AF: 0.00170 AC: 26 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4830

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00210 AC: 143 AN: 68046

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000742 Hom.: 0

Bravo AF: 0.00135

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Diamond-Blackfan anemia 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	24
DANN	Benign	0.84
PhyloP100		4.6
PromoterAI		-0.33	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.0
Mutation Taster		=272/28	polymorphism

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

Other links and lift over

dbSNP: rs564722971; hg19: chr3-197677092;