10-125815034-C-G

Variant names:

• chr10-125815034-C-G
• rs121908016
• NM_000375.3:c.244G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000375.3(UROS):​c.244G>C​(p.Val82Leu) variant causes a missense, splice region change. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V82F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UROS NM_000375.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.69
• Publications: 0 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: Likely_pathogenic. The variant received 6 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UROS	NM_000375.3	c.244G>C	p.Val82Leu	missense_variant, splice_region_variant	Exon 4 of 10	ENST00000368797.10	NP_000366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UROS	ENST00000368797.10	c.244G>C	p.Val82Leu	missense_variant, splice_region_variant	Exon 4 of 10	1	NM_000375.3	ENSP00000357787.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;T;T;.;.;T;T;T
Eigen	Benign	-0.085
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.0	.;.;D;D;D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.037	T
MutationAssessor	Benign	0.76	N;N;N;.;.;.;.;.
PhyloP100		3.7
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.53	N;.;N;.;.;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.27	T;.;T;.;.;T;T;T
Sift4G	Benign	0.30	T;.;T;.;.;.;T;T
Vest4		0.11
ClinPred		0.53	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.37
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: 0

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

Other links and lift over

dbSNP: rs121908016; hg19: chr10-127503603;