9-135500990-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_016034.5(MRPS2):c.44-8C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,611,258 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: MRPS2 NM_016034.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004455
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.20

Genes affected

MRPS2 (HGNC:14495): (mitochondrial ribosomal protein S2) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein that belongs to the ribosomal protein S2 family. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, May 2012]

PIERCE1 (HGNC:28435): (piercer of microtubule wall 1) Predicted to act upstream of or within several processes, including cellular response to DNA damage stimulus; cellular response to UV-C; and determination of left/right symmetry. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046519578).
• BP6: Variant 9-135500990-C-A is Benign according to our data. Variant chr9-135500990-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1542228.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPS2	NM_016034.5	c.44-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000241600.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPS2	ENST00000241600.10	c.44-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_016034.5	P1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 151954 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000214 AC: 52 AN: 242848 Hom.: 0 AF XY: 0.000158 AC XY: 21 AN XY: 133254

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00142

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000570

Gnomad NFE exome AF: 0.000231

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000208 AC: 304 AN: 1459304 Hom.: 0 Cov.: 30 AF XY: 0.000233 AC XY: 169 AN XY: 725986

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000865

Gnomad4 NFE exome AF: 0.000186

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000217 AC: 33 AN: 151954 Hom.: 0 Cov.: 33 AF XY: 0.000189 AC XY: 14 AN XY: 74198

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000371 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.000249 AC: 30

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	6.2
Dann	Benign	0.80
Eigen	Benign	0.053
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.90	N;N;N
PROVEAN	Benign	0.16	N
REVEL	Benign	0.038
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.32	T
MutPred		0.26		Loss of sheet (P = 0.0025);
MVP		0.65
ClinPred		0.077	T
GERP RS		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00045
dbscSNV1_RF	Benign	0.072
SpliceAI score (max)		0.020		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: rs201279394; hg19: chr9-138392836;