12-56042167-A-C

Position:

• chr12-56042167-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001029.5(RPS26):​c.1A>C​(p.Met1?) variant causes a start lost, splice region change. 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 predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS26 NM_001029.5 start_lost, splice_region
• Scores: Splicing: ADA: 0.04704
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.53

Genes affected

RPS26 (HGNC:10414): (ribosomal protein S26) This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S26E family of ribosomal proteins. Mutations in this gene are found in Diamond-Blackfan anemia 10. There are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-56042167-A-C is Pathogenic according to our data. Variant chr12-56042167-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 598993.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS26	NM_001029.5	c.1A>C	p.Met1?	start_lost, splice_region_variant	1/4	ENST00000646449.2	NP_001020.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS26	ENST00000646449.2	c.1A>C	p.Met1?	start_lost, splice_region_variant	1/4		NM_001029.5	ENSP00000496643	P1
RPS26	ENST00000356464.10	c.1A>C	p.Met1?	start_lost, splice_region_variant	2/5	1		ENSP00000348849	P1
RPS26	ENST00000552361.1	c.1A>C	p.Met1?	start_lost, splice_region_variant	2/5	5		ENSP00000450339	P1
RPS26	ENST00000548590.1	n.28A>C		splice_region_variant, non_coding_transcript_exon_variant	1/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Bone marrow hypocellularity Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

-

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

Dec 21, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.22	T;T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	.;.;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.74	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Uncertain	-2.4	N;N;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.023	D;D;.
Sift4G	Uncertain	0.0070	D;D;.
Polyphen		0.13	B;B;B
Vest4		0.93
MutPred		0.82		Loss of methylation at K3 (P = 0.0455);Loss of methylation at K3 (P = 0.0455);Loss of methylation at K3 (P = 0.0455);
MVP		1.0
ClinPred		0.83	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.047
dbscSNV1_RF	Benign	0.30
SpliceAI score (max)		0.010		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: rs143951267; hg19: chr12-56435951;