chr10-125796685-A-G

Variant names:

• chr10-125796685-A-G
• rs1571278
• NM_000375.3:c.476-497T>C

Variant summary

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

The NM_001324036.2(UROS):​c.476-497T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 729,002 control chromosomes in the GnomAD database, including 76,929 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 0.43 (14179 hom., cov: 32)
  • Exomes 𝑓: 0.46 (62750 hom.)
• Consequence: UROS NM_001324036.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.148
• Publications: 17 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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001324036.2. 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.476-497T>C		intron	N/A	NP_000366.1
	UROS	NM_001324036.2		c.476-497T>C		intron	N/A	NP_001310965.1
	UROS	NM_001324037.2		c.395-497T>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.476-497T>C		intron	N/A	ENSP00000357787.4
	UROS	ENST00000368786.5	TSL:1	c.476-497T>C		intron	N/A	ENSP00000357775.1
	UROS	ENST00000940865.1		c.575-497T>C		intron	N/A	ENSP00000610924.1

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65140 AN: 151900 Hom.: 14167 Cov.: 32

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.427

GnomAD4 exome AF: 0.464 AC: 267471 AN: 576984 Hom.: 62750 AF XY: 0.464 AC XY: 125299 AN XY: 270058

African (AFR) AF: 0.425 AC: 4475 AN: 10538

American (AMR) AF: 0.275 AC: 179 AN: 652

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1430 AN: 3502

East Asian (EAS) AF: 0.277 AC: 664 AN: 2396

South Asian (SAS) AF: 0.401 AC: 4539 AN: 11314

European-Finnish (FIN) AF: 0.410 AC: 77 AN: 188

Middle Eastern (MID) AF: 0.352 AC: 388 AN: 1102

European-Non Finnish (NFE) AF: 0.468 AC: 247470 AN: 528422

Other (OTH) AF: 0.437 AC: 8249 AN: 18870

GnomAD4 genome AF: 0.429 AC: 65181 AN: 152018 Hom.: 14179 Cov.: 32 AF XY: 0.423 AC XY: 31407 AN XY: 74280

African (AFR) AF: 0.430 AC: 17815 AN: 41460

American (AMR) AF: 0.336 AC: 5129 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1386 AN: 3470

East Asian (EAS) AF: 0.293 AC: 1511 AN: 5152

South Asian (SAS) AF: 0.398 AC: 1918 AN: 4816

European-Finnish (FIN) AF: 0.432 AC: 4559 AN: 10560

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.462 AC: 31397 AN: 67962

Other (OTH) AF: 0.429 AC: 904 AN: 2108

Alfa AF: 0.426 Hom.: 10431

Bravo AF: 0.420

Asia WGS AF: 0.363 AC: 1263 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.9
DANN	Benign	0.55
PhyloP100		-0.15
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: rs1571278; hg19: chr10-127485254;