NM_001029.5:c.1A>C

Variant names:

• chr12-56042167-A-C
• rs143951267
• NM_001029.5:c.1A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001029.5(RPS26):​c.1A>C​(p.Met1?) variant causes a initiator codon, 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 initiator_codon, splice_region
• Scores: Splicing: ADA: 0.04704
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.53
• Publications: 6 publications found

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]

RPS26 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia 10

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId is 598993.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001029.5. 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
	RPS26	NM_001029.5	MANE Select	c.1A>C	p.Met1?	initiator_codon splice_region	Exon 1 of 4	NP_001020.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS26	ENST00000646449.2	MANE Select	c.1A>C	p.Met1?	initiator_codon splice_region	Exon 1 of 4	ENSP00000496643.1	P62854
	RPS26	ENST00000356464.10	TSL:1	c.1A>C	p.Met1?	initiator_codon splice_region	Exon 2 of 5	ENSP00000348849.5	P62854
	RPS26	ENST00000552361.1	TSL:5	c.1A>C	p.Met1?	initiator_codon splice_region	Exon 2 of 5	ENSP00000450339.1	P62854

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	0.74	D
PhyloP100		4.5
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.13	B
Vest4		0.93
MutPred		0.82		Loss of methylation at K3 (P = 0.0455)
MVP		1.0
ClinPred		0.83	D
GERP RS		5.9
PromoterAI		-0.54	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.63
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs143951267; hg19: chr12-56435951;