NM_000375.3:c.562-417A>G

Variant names:

• chr10-125795395-T-C
• rs10751533
• NM_000375.3:c.562-417A>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.562-417A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 152,148 control chromosomes in the GnomAD database, including 15,990 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 0.45 (15990 hom., cov: 33)
• Consequence: UROS NM_000375.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.289
• Publications: 11 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UROS	NM_000375.3	c.562-417A>G		intron_variant	Intron 8 of 9	ENST00000368797.10	NP_000366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UROS	ENST00000368797.10	c.562-417A>G		intron_variant	Intron 8 of 9	1	NM_000375.3	ENSP00000357787.4

Frequencies

GnomAD3 genomes AF: 0.455 AC: 69121 AN: 152030 Hom.: 15975 Cov.: 33

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.538

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.450

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

GnomAD4 genome AF: 0.455 AC: 69173 AN: 152148 Hom.: 15990 Cov.: 33 AF XY: 0.449 AC XY: 33372 AN XY: 74372

African (AFR) AF: 0.509 AC: 21132 AN: 41508

American (AMR) AF: 0.341 AC: 5212 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1359 AN: 3468

East Asian (EAS) AF: 0.321 AC: 1661 AN: 5174

South Asian (SAS) AF: 0.455 AC: 2197 AN: 4830

European-Finnish (FIN) AF: 0.429 AC: 4547 AN: 10588

Middle Eastern (MID) AF: 0.312 AC: 91 AN: 292

European-Non Finnish (NFE) AF: 0.464 AC: 31527 AN: 67974

Other (OTH) AF: 0.452 AC: 956 AN: 2114

Alfa AF: 0.454 Hom.: 2738

Bravo AF: 0.447

Asia WGS AF: 0.398 AC: 1385 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	4.7
DANN	Benign	0.66
PhyloP100		0.29
Mutation Taster		=100/0	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: rs10751533; hg19: chr10-127483964; COSMIC: COSV64230056; COSMIC: COSV64230056;