10-125802596-C-T

Variant names:

• chr10-125802596-C-T
• rs3814624
• NM_000375.3:c.395-4451G>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.395-4451G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 1,031,042 control chromosomes in the GnomAD database, including 108,350 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 (13561 hom., cov: 33)
  • Exomes 𝑓: 0.46 (94789 hom.)
• Consequence: UROS NM_000375.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• 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=-0.85).
• 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.395-4451G>A		intron_variant	Intron 6 of 9	ENST00000368797.10	NP_000366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UROS	ENST00000368797.10	c.395-4451G>A		intron_variant	Intron 6 of 9	1	NM_000375.3	ENSP00000357787.4

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63537 AN: 152030 Hom.: 13545 Cov.: 33

Gnomad AFR AF: 0.389

Gnomad AMI AF: 0.538

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.420

GnomAD4 exome AF: 0.463 AC: 407284 AN: 878894 Hom.: 94789 Cov.: 32 AF XY: 0.463 AC XY: 189222 AN XY: 408288

African (AFR) AF: 0.385 AC: 6586 AN: 17116

American (AMR) AF: 0.267 AC: 1042 AN: 3896

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 2500 AN: 6452

East Asian (EAS) AF: 0.287 AC: 1701 AN: 5930

South Asian (SAS) AF: 0.425 AC: 8913 AN: 20968

European-Finnish (FIN) AF: 0.423 AC: 809 AN: 1914

Middle Eastern (MID) AF: 0.358 AC: 647 AN: 1808

European-Non Finnish (NFE) AF: 0.470 AC: 371884 AN: 790678

Other (OTH) AF: 0.438 AC: 13202 AN: 30132

GnomAD4 genome AF: 0.418 AC: 63584 AN: 152148 Hom.: 13561 Cov.: 33 AF XY: 0.413 AC XY: 30704 AN XY: 74384

African (AFR) AF: 0.388 AC: 16114 AN: 41478

American (AMR) AF: 0.331 AC: 5059 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1352 AN: 3472

East Asian (EAS) AF: 0.299 AC: 1550 AN: 5176

South Asian (SAS) AF: 0.425 AC: 2050 AN: 4824

European-Finnish (FIN) AF: 0.429 AC: 4541 AN: 10582

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

European-Non Finnish (NFE) AF: 0.462 AC: 31446 AN: 68002

Other (OTH) AF: 0.423 AC: 892 AN: 2110

Alfa AF: 0.432 Hom.: 2998

Bravo AF: 0.406

Asia WGS AF: 0.373 AC: 1299 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.6
DANN	Benign	0.45
PhyloP100		1.0
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: rs3814624; hg19: chr10-127491165;