NM_000375.3:c.743C>A

Variant names:

• chr10-125788923-G-T
• rs121908021
• NM_000375.3:c.743C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000375.3(UROS):​c.743C>A​(p.Pro248Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: UROS NM_000375.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.79
• Publications: 14 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 10-125788923-G-T is Pathogenic according to our data. Variant chr10-125788923-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3769.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROS	NM_000375.3	MANE Select	c.743C>A	p.Pro248Gln	missense	Exon 10 of 10	NP_000366.1	A0A0S2Z4T8
	UROS	NM_001324036.2		c.824C>A	p.Pro275Gln	missense	Exon 11 of 11	NP_001310965.1	A0A3B3ISM6
	UROS	NM_001324037.2		c.743C>A	p.Pro248Gln	missense	Exon 10 of 10	NP_001310966.1	A0A3B3ITJ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROS	ENST00000368797.10	TSL:1 MANE Select	c.743C>A	p.Pro248Gln	missense	Exon 10 of 10	ENSP00000357787.4	P10746
	UROS	ENST00000368786.5	TSL:1	c.743C>A	p.Pro248Gln	missense	Exon 9 of 9	ENSP00000357775.1	P10746
	UROS	ENST00000940865.1		c.923C>A	p.Pro308Gln	missense	Exon 11 of 11	ENSP00000610924.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456448 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724142

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 43920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25884

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 85130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110796

Other (OTH) AF: 0.0000166 AC: 1 AN: 60158

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.8
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.84		Loss of glycosylation at P248 (P = 0.0489)
MVP		0.94
MPC		0.45
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.77
gMVP		0.81
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908021; hg19: chr10-127477492;