NM_000375.3:c.319+2228G>A

Variant names:

• chr10-125809986-C-T
• rs10794025
• NM_000375.3:c.319+2228G>A

Variant summary

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

The NM_000375.3(UROS):​c.319+2228G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 152,076 control chromosomes in the GnomAD database, including 13,820 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 0.42 (13820 hom., cov: 33)
• Consequence: UROS NM_000375.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.27
• 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=-0.92).
• 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.319+2228G>A		intron	N/A	NP_000366.1
	UROS	NM_001324036.2		c.319+2228G>A		intron	N/A	NP_001310965.1
	UROS	NM_001324037.2		c.319+2228G>A		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.319+2228G>A		intron	N/A	ENSP00000357787.4
	UROS	ENST00000368786.5	TSL:1	c.319+2228G>A		intron	N/A	ENSP00000357775.1
	UROS	ENST00000650587.1		c.319+2228G>A		intron	N/A	ENSP00000497366.1

Frequencies

GnomAD3 genomes AF: 0.422 AC: 64118 AN: 151958 Hom.: 13804 Cov.: 33

Gnomad AFR AF: 0.398

Gnomad AMI AF: 0.538

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.422

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

GnomAD4 genome AF: 0.422 AC: 64166 AN: 152076 Hom.: 13820 Cov.: 33 AF XY: 0.416 AC XY: 30944 AN XY: 74332

African (AFR) AF: 0.398 AC: 16511 AN: 41476

American (AMR) AF: 0.332 AC: 5072 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1354 AN: 3470

East Asian (EAS) AF: 0.292 AC: 1508 AN: 5164

South Asian (SAS) AF: 0.414 AC: 1998 AN: 4828

European-Finnish (FIN) AF: 0.429 AC: 4542 AN: 10576

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

European-Non Finnish (NFE) AF: 0.466 AC: 31705 AN: 67970

Other (OTH) AF: 0.425 AC: 897 AN: 2112

Alfa AF: 0.433 Hom.: 2510

Bravo AF: 0.411

Asia WGS AF: 0.367 AC: 1279 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.23
DANN	Benign	0.48
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: rs10794025; hg19: chr10-127498555;