rs886046814

Variant names:

• chr10-125788769-T-C
• rs886046814
• NM_000375.3:c.*99A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-125788769-T-C
• chr10-125788769-T-G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000375.3(UROS):​c.*99A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,481,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: UROS NM_000375.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.60
• Publications: 0 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, G2P, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000853 (13/152362) while in subpopulation EAS AF = 0.00251 (13/5184). AF 95% confidence interval is 0.00148. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*99A>G		3_prime_UTR	Exon 10 of 10	NP_000366.1	A0A0S2Z4T8
	UROS	NM_001324036.2		c.*99A>G		3_prime_UTR	Exon 11 of 11	NP_001310965.1	A0A3B3ISM6
	UROS	NM_001324037.2		c.*99A>G		3_prime_UTR	Exon 10 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.*99A>G		3_prime_UTR	Exon 10 of 10	ENSP00000357787.4	P10746
	UROS	ENST00000368786.5	TSL:1	c.*99A>G		3_prime_UTR	Exon 9 of 9	ENSP00000357775.1	P10746
	UROS	ENST00000940865.1		c.*99A>G		3_prime_UTR	Exon 11 of 11	ENSP00000610924.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000595 AC: 79 AN: 1328802 Hom.: 0 Cov.: 30 AF XY: 0.0000463 AC XY: 30 AN XY: 648204

African (AFR) AF: 0.00 AC: 0 AN: 29946

American (AMR) AF: 0.00 AC: 0 AN: 28582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21002

East Asian (EAS) AF: 0.00185 AC: 65 AN: 35096

South Asian (SAS) AF: 0.00 AC: 0 AN: 70248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3764

European-Non Finnish (NFE) AF: 0.00000286 AC: 3 AN: 1047234

Other (OTH) AF: 0.000200 AC: 11 AN: 54980

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74502

African (AFR) AF: 0.00 AC: 0 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000162

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cutaneous porphyria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.083
DANN	Benign	0.49
PhyloP100		-2.6

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: rs886046814; hg19: chr10-127477338;