NM_000375.3:c.394+785A>G

Variant names:

• chr10-125806628-T-C
• rs12251135
• NM_000375.3:c.394+785A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000375.3(UROS):​c.394+785A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 152,216 control chromosomes in the GnomAD database, including 7,235 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (7235 hom., cov: 33)
• Consequence: UROS NM_000375.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.272
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UROS	NM_000375.3	c.394+785A>G		intron_variant	Intron 6 of 9	ENST00000368797.10	NP_000366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UROS	ENST00000368797.10	c.394+785A>G		intron_variant	Intron 6 of 9	1	NM_000375.3	ENSP00000357787.4

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45934 AN: 152098 Hom.: 7236 Cov.: 33

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.354

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.292

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.302 AC: 45955 AN: 152216 Hom.: 7235 Cov.: 33 AF XY: 0.309 AC XY: 22966 AN XY: 74422

African (AFR) AF: 0.218 AC: 9076 AN: 41538

American (AMR) AF: 0.290 AC: 4442 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 1230 AN: 3470

East Asian (EAS) AF: 0.413 AC: 2137 AN: 5172

South Asian (SAS) AF: 0.362 AC: 1744 AN: 4824

European-Finnish (FIN) AF: 0.409 AC: 4333 AN: 10590

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.324 AC: 22037 AN: 68002

Other (OTH) AF: 0.292 AC: 616 AN: 2110

Alfa AF: 0.314 Hom.: 20916

Bravo AF: 0.291

Asia WGS AF: 0.363 AC: 1266 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.56
DANN	Benign	0.57
PhyloP100		-0.27
Mutation Taster		=99/1	polymorphism (auto)

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: rs12251135; hg19: chr10-127495197;