rs397515527

Variant names:

• chr10-125816185-A-G
• rs397515527
• NM_000375.3:c.139T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UROS NM_000375.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 3.10
• Publications: 7 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: ClinGen, G2P, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant 10-125816185-A-G is Pathogenic according to our data. Variant chr10-125816185-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 65600.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROS	NM_000375.3	MANE Select	c.139T>C	p.Ser47Pro	missense	Exon 3 of 10	NP_000366.1
	UROS	NM_001324036.2		c.139T>C	p.Ser47Pro	missense	Exon 3 of 11	NP_001310965.1
	UROS	NM_001324037.2		c.139T>C	p.Ser47Pro	missense	Exon 3 of 10	NP_001310966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROS	ENST00000368797.10	TSL:1 MANE Select	c.139T>C	p.Ser47Pro	missense	Exon 3 of 10	ENSP00000357787.4
	UROS	ENST00000368786.5	TSL:1	c.139T>C	p.Ser47Pro	missense	Exon 2 of 9	ENSP00000357775.1
	UROS	ENST00000940865.1		c.139T>C	p.Ser47Pro	missense	Exon 3 of 11	ENSP00000610924.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cutaneous porphyria (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.2	L
PhyloP100		3.1
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.70
Sift	Benign	0.15	T
Sift4G	Benign	0.28	T
Polyphen		1.0	D
Vest4		0.45
MutPred		0.81		Loss of phosphorylation at S47 (P = 0.0445)
MVP		0.91
MPC		0.46
ClinPred		0.93	D
GERP RS		4.5
PromoterAI		0.0063	Neutral
Varity_R		0.96
gMVP		0.73
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs397515527; hg19: chr10-127504754;