rs2149019

Variant names:

• chr10-125794381-G-A
• rs2149019
• NM_000375.3:c.660+499C>T

Variant summary

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

The NM_000375.3(UROS):​c.660+499C>T 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 1,004,508 control chromosomes in the GnomAD database, including 105,303 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 (13091 hom., cov: 32)
  • Exomes 𝑓: 0.46 (92212 hom.)
• Consequence: UROS NM_000375.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0230
• Publications: 15 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=-0.6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UROS	NM_000375.3	c.660+499C>T		intron_variant	Intron 9 of 9	ENST00000368797.10	NP_000366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UROS	ENST00000368797.10	c.660+499C>T		intron_variant	Intron 9 of 9	1	NM_000375.3	ENSP00000357787.4

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62285 AN: 151910 Hom.: 13083 Cov.: 32

Gnomad AFR AF: 0.363

Gnomad AMI AF: 0.537

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.404

GnomAD4 exome AF: 0.464 AC: 395295 AN: 852480 Hom.: 92212 Cov.: 27 AF XY: 0.464 AC XY: 183347 AN XY: 395462

African (AFR) AF: 0.364 AC: 5785 AN: 15900

American (AMR) AF: 0.255 AC: 844 AN: 3308

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 2069 AN: 5446

East Asian (EAS) AF: 0.274 AC: 1208 AN: 4404

South Asian (SAS) AF: 0.417 AC: 7859 AN: 18842

European-Finnish (FIN) AF: 0.398 AC: 345 AN: 866

Middle Eastern (MID) AF: 0.360 AC: 607 AN: 1684

European-Non Finnish (NFE) AF: 0.471 AC: 364205 AN: 773828

Other (OTH) AF: 0.439 AC: 12373 AN: 28202

GnomAD4 genome AF: 0.410 AC: 62319 AN: 152028 Hom.: 13091 Cov.: 32 AF XY: 0.405 AC XY: 30128 AN XY: 74310

African (AFR) AF: 0.362 AC: 15017 AN: 41440

American (AMR) AF: 0.326 AC: 4986 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 1316 AN: 3472

East Asian (EAS) AF: 0.300 AC: 1550 AN: 5166

South Asian (SAS) AF: 0.425 AC: 2047 AN: 4818

European-Finnish (FIN) AF: 0.429 AC: 4524 AN: 10554

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.463 AC: 31445 AN: 67984

Other (OTH) AF: 0.407 AC: 857 AN: 2108

Alfa AF: 0.425 Hom.: 2193

Bravo AF: 0.398

Asia WGS AF: 0.370 AC: 1288 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.92
PhyloP100		0.023
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2149019; hg19: chr10-127482950;