10-125820725-G-C

Variant names:

• chr10-125820725-G-C
• rs10901450
• NM_000375.3:c.-27+2304C>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.-27+2304C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 152,068 control chromosomes in the GnomAD database, including 13,162 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 0.41 (13162 hom., cov: 32)
• Consequence: UROS NM_000375.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0430
• Publications: 13 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 (NFE) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROS	NM_000375.3	MANE Select	c.-27+2304C>G		intron	N/A	NP_000366.1
	UROS	NM_001324036.2		c.-27+2304C>G		intron	N/A	NP_001310965.1
	UROS	NM_001324037.2		c.-27+2304C>G		intron	N/A	NP_001310966.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROS	ENST00000368797.10	TSL:1 MANE Select	c.-27+2304C>G		intron	N/A	ENSP00000357787.4
	UROS	ENST00000649536.1		c.-27+2304C>G		intron	N/A	ENSP00000497817.1
	UROS	ENST00000713579.1		c.-27+2304C>G		intron	N/A	ENSP00000518871.1

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62318 AN: 151950 Hom.: 13148 Cov.: 32

Gnomad AFR AF: 0.358

Gnomad AMI AF: 0.538

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.414

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.415

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

GnomAD4 genome AF: 0.410 AC: 62362 AN: 152068 Hom.: 13162 Cov.: 32 AF XY: 0.405 AC XY: 30136 AN XY: 74342

African (AFR) AF: 0.358 AC: 14825 AN: 41450

American (AMR) AF: 0.325 AC: 4968 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1355 AN: 3470

East Asian (EAS) AF: 0.292 AC: 1508 AN: 5160

South Asian (SAS) AF: 0.414 AC: 1997 AN: 4820

European-Finnish (FIN) AF: 0.430 AC: 4543 AN: 10576

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.466 AC: 31706 AN: 67984

Other (OTH) AF: 0.418 AC: 881 AN: 2108

Alfa AF: 0.449 Hom.: 2120

Bravo AF: 0.397

Asia WGS AF: 0.366 AC: 1273 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.4
DANN	Benign	0.58
PhyloP100		-0.043
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: rs10901450; hg19: chr10-127509294;