rs4385801

Variant names:

• chr10-125823221-G-T
• rs4385801
• NM_000375.3:c.-219C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-125823221-G-T
• chr10-125823221-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000375.3(UROS):​c.-219C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 221,424 control chromosomes in the GnomAD database, including 21,324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13475 hom., cov: 35)
  • Exomes 𝑓: 0.47 (7849 hom.)
• Consequence: UROS NM_000375.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -2.01
• Publications: 14 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: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 10-125823221-G-T is Benign according to our data. Variant chr10-125823221-G-T is described in ClinVar as Benign. ClinVar VariationId is 225268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROS	NM_000375.3	MANE Select	c.-219C>A		5_prime_UTR	Exon 1 of 10	NP_000366.1	A0A0S2Z4T8
	UROS	NM_001324036.2		c.-219C>A		5_prime_UTR	Exon 1 of 11	NP_001310965.1	A0A3B3ISM6
	UROS	NM_001324037.2		c.-219C>A		5_prime_UTR	Exon 1 of 10	NP_001310966.1	A0A3B3ITJ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROS	ENST00000368797.10	TSL:1 MANE Select	c.-219C>A		5_prime_UTR	Exon 1 of 10	ENSP00000357787.4	P10746
	UROS	ENST00000940865.1		c.-219C>A		5_prime_UTR	Exon 1 of 11	ENSP00000610924.1
	UROS	ENST00000879953.1		c.-219C>A		5_prime_UTR	Exon 1 of 11	ENSP00000550012.1

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63184 AN: 152020 Hom.: 13460 Cov.: 35

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.537

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.418

GnomAD4 exome AF: 0.470 AC: 32543 AN: 69286 Hom.: 7849 Cov.: 0 AF XY: 0.469 AC XY: 16698 AN XY: 35638

African (AFR) AF: 0.382 AC: 782 AN: 2046

American (AMR) AF: 0.338 AC: 789 AN: 2334

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1108 AN: 2642

East Asian (EAS) AF: 0.356 AC: 1706 AN: 4794

South Asian (SAS) AF: 0.477 AC: 2458 AN: 5152

European-Finnish (FIN) AF: 0.469 AC: 1688 AN: 3600

Middle Eastern (MID) AF: 0.354 AC: 112 AN: 316

European-Non Finnish (NFE) AF: 0.500 AC: 21948 AN: 43902

Other (OTH) AF: 0.434 AC: 1952 AN: 4500

GnomAD4 genome AF: 0.416 AC: 63229 AN: 152138 Hom.: 13475 Cov.: 35 AF XY: 0.411 AC XY: 30540 AN XY: 74392

African (AFR) AF: 0.377 AC: 15651 AN: 41522

American (AMR) AF: 0.329 AC: 5029 AN: 15300

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

East Asian (EAS) AF: 0.292 AC: 1504 AN: 5144

South Asian (SAS) AF: 0.412 AC: 1986 AN: 4824

European-Finnish (FIN) AF: 0.428 AC: 4541 AN: 10606

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

European-Non Finnish (NFE) AF: 0.466 AC: 31698 AN: 67958

Other (OTH) AF: 0.421 AC: 888 AN: 2110

Alfa AF: 0.338 Hom.: 952

Bravo AF: 0.404

Asia WGS AF: 0.363 AC: 1266 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cutaneous porphyria (3)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.42
DANN	Benign	0.79
PhyloP100		-2.0
PromoterAI		0.042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs4385801; hg19: chr10-127511790;