chr10-125816185-A-G

Position:

• chr10-125816185-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000375.3(UROS):​c.139T>C​(p.Ser47Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UROS NM_000375.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 3.10

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: MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UROS	NM_000375.3	c.139T>C	p.Ser47Pro	missense_variant	3/10	ENST00000368797.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UROS	ENST00000368797.10	c.139T>C	p.Ser47Pro	missense_variant	3/10	1	NM_000375.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Cutaneous porphyria Other:1

not provided, no classification provided

literature only

GeneReviews

-

Associated with a severe CEP phenotype; however, in 1 family with 5 children homozygous for this variant, 4 children had severe clinical findings while 1 had very mild cutaneous findings. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D;D;.;.;D;D
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.83	.;.;T;T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.2	L;L;L;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.2	N;.;N;.;.;N;N
REVEL	Pathogenic	0.70
Sift	Benign	0.15	T;.;T;.;.;T;T
Sift4G	Benign	0.28	T;.;T;.;.;T;T
Polyphen		1.0	D;D;D;.;.;.;.
Vest4		0.45
MutPred		0.81		Loss of phosphorylation at S47 (P = 0.0445);Loss of phosphorylation at S47 (P = 0.0445);Loss of phosphorylation at S47 (P = 0.0445);Loss of phosphorylation at S47 (P = 0.0445);Loss of phosphorylation at S47 (P = 0.0445);Loss of phosphorylation at S47 (P = 0.0445);Loss of phosphorylation at S47 (P = 0.0445);
MVP		0.91
MPC		0.46
ClinPred		0.93	D
GERP RS		4.5
Varity_R		0.96
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397515527; hg19: chr10-127504754;