10-125806584-T-G

Variant names:

• chr10-125806584-T-G
• rs1891359
• NM_000375.3:c.394+829A>C

Variant summary

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

The ENST00000368797.10(UROS):​c.394+829A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 152,312 control chromosomes in the GnomAD database, including 1,284 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 0.11 (1284 hom., cov: 33)
• Consequence: UROS ENST00000368797.10 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.30
• Publications: 2 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000368797.10. 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.394+829A>C		intron	N/A	NP_000366.1
	UROS	NM_001324036.2		c.394+829A>C		intron	N/A	NP_001310965.1
	UROS	NM_001324037.2		c.394+829A>C		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.394+829A>C		intron	N/A	ENSP00000357787.4
	UROS	ENST00000368786.5	TSL:1	c.394+829A>C		intron	N/A	ENSP00000357775.1
	UROS	ENST00000650587.1		c.394+829A>C		intron	N/A	ENSP00000497366.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16326 AN: 152194 Hom.: 1284 Cov.: 33

Gnomad AFR AF: 0.0473

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.0809

Gnomad FIN AF: 0.0565

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.137

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

GnomAD4 genome AF: 0.107 AC: 16333 AN: 152312 Hom.: 1284 Cov.: 33 AF XY: 0.107 AC XY: 8003 AN XY: 74476

African (AFR) AF: 0.0472 AC: 1962 AN: 41584

American (AMR) AF: 0.276 AC: 4216 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 462 AN: 3470

East Asian (EAS) AF: 0.0237 AC: 123 AN: 5186

South Asian (SAS) AF: 0.0808 AC: 390 AN: 4828

European-Finnish (FIN) AF: 0.0565 AC: 600 AN: 10612

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8061 AN: 68030

Other (OTH) AF: 0.135 AC: 286 AN: 2112

Alfa AF: 0.0438 Hom.: 36

Bravo AF: 0.123

Asia WGS AF: 0.0820 AC: 285 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.21
DANN	Benign	0.83
PhyloP100		-1.3
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: rs1891359; hg19: chr10-127495153;