rs121908018

Positions:

• chr10-125815035-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Uroporphyrinogen-III synthase (size 264) in uniprot entity HEM4_HUMAN there are 25 pathogenic changes around while only 9 benign (74%) in NM_000375.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius 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 id is 3760.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UROS	NM_000375.3	c.243A>T	p.Glu81Asp	missense_variant, splice_region_variant	4/10	ENST00000368797.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UROS	ENST00000368797.10	c.243A>T	p.Glu81Asp	missense_variant, splice_region_variant	4/10	1	NM_000375.3	P1

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

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;D;D;.;.;T;T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.017
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	.;.;T;T;T;T;T;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.7	L;L;L;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.96	N;.;N;.;.;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.17	T;.;T;.;.;T;T;T
Sift4G	Uncertain	0.032	D;.;D;.;.;.;D;D
Polyphen		0.0030	B;B;B;.;.;.;.;.
Vest4		0.22
MutPred		0.35		Loss of ubiquitination at K79 (P = 0.0738);Loss of ubiquitination at K79 (P = 0.0738);Loss of ubiquitination at K79 (P = 0.0738);Loss of ubiquitination at K79 (P = 0.0738);Loss of ubiquitination at K79 (P = 0.0738);.;Loss of ubiquitination at K79 (P = 0.0738);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908018; hg19: chr10-127503604;