rs121908018

Variant names:

• chr10-125815035-T-A
• rs121908018
• NM_000375.3:c.243A>T

Your query was ambiguous. Multiple possible variants found:

• chr10-125815035-T-A
• chr10-125815035-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000375.3(UROS):​c.243A>T​(p.Glu81Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UROS NM_000375.3 missense, splice_region
• Scores: Splicing: ADA: 0.9963
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.78
• Publications: 4 publications found

Genes affected

UROS (HGNC:12592): (uroporphyrinogen III synthase) The protein encoded by this gene catalyzes the fourth step of porphyrin biosynthesis in the heme biosynthetic pathway. Defects in this gene cause congenital erythropoietic porphyria (Gunther's disease). [provided by RefSeq, Jul 2008]

UROS Gene-Disease associations (from GenCC):

• cutaneous porphyria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 10-125815035-T-A is Pathogenic according to our data. Variant chr10-125815035-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3760.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000375.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROS	NM_000375.3	MANE Select	c.243A>T	p.Glu81Asp	missense splice_region	Exon 4 of 10	NP_000366.1
	UROS	NM_001324036.2		c.243A>T	p.Glu81Asp	missense splice_region	Exon 4 of 11	NP_001310965.1
	UROS	NM_001324037.2		c.243A>T	p.Glu81Asp	missense splice_region	Exon 4 of 10	NP_001310966.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROS	ENST00000368797.10	TSL:1 MANE Select	c.243A>T	p.Glu81Asp	missense splice_region	Exon 4 of 10	ENSP00000357787.4
	UROS	ENST00000368786.5	TSL:1	c.243A>T	p.Glu81Asp	missense splice_region	Exon 3 of 9	ENSP00000357775.1
	UROS	ENST00000650587.1		c.243A>T	p.Glu81Asp	missense splice_region	Exon 3 of 10	ENSP00000497366.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cutaneous porphyria Pathogenic:1

Jun 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.12
Eigen_PC	Benign	0.017
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.7	L
PhyloP100		2.8
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.36
Sift	Benign	0.17	T
Sift4G	Uncertain	0.032	D
Polyphen		0.0030	B
Vest4		0.22
MutPred		0.35		Loss of ubiquitination at K79 (P = 0.0738)
MVP		0.90
MPC		0.080
ClinPred		0.73	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.44
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.57		Position offset: -1

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

Other links and lift over

dbSNP: rs121908018; hg19: chr10-127503604;