NM_000375.3:c.*96G>A

Variant names:

• chr10-125788772-C-T
• rs182303293
• NM_000375.3:c.*96G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000375.3(UROS):​c.*96G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000435 in 1,484,116 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (6 hom.)
• Consequence: UROS NM_000375.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.909
• 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 10-125788772-C-T is Benign according to our data. Variant chr10-125788772-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 877580.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000637 (97/152364) while in subpopulation EAS AF = 0.0157 (81/5174). AF 95% confidence interval is 0.0129. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

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.*96G>A		3_prime_UTR	Exon 10 of 10	NP_000366.1	A0A0S2Z4T8
	UROS	NM_001324036.2		c.*96G>A		3_prime_UTR	Exon 11 of 11	NP_001310965.1	A0A3B3ISM6
	UROS	NM_001324037.2		c.*96G>A		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.*96G>A		3_prime_UTR	Exon 10 of 10	ENSP00000357787.4	P10746
	UROS	ENST00000368786.5	TSL:1	c.*96G>A		3_prime_UTR	Exon 9 of 9	ENSP00000357775.1	P10746
	UROS	ENST00000940865.1		c.*96G>A		3_prime_UTR	Exon 11 of 11	ENSP00000610924.1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000412 AC: 549 AN: 1331752 Hom.: 6 Cov.: 30 AF XY: 0.000411 AC XY: 267 AN XY: 649942

African (AFR) AF: 0.00 AC: 0 AN: 30018

American (AMR) AF: 0.0000690 AC: 2 AN: 28996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21218

East Asian (EAS) AF: 0.00885 AC: 311 AN: 35122

South Asian (SAS) AF: 0.000692 AC: 49 AN: 70768

European-Finnish (FIN) AF: 0.0000260 AC: 1 AN: 38480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3778

European-Non Finnish (NFE) AF: 0.0000696 AC: 73 AN: 1048300

Other (OTH) AF: 0.00205 AC: 113 AN: 55072

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74510

African (AFR) AF: 0.00 AC: 0 AN: 41592

American (AMR) AF: 0.000131 AC: 2 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0157 AC: 81 AN: 5174

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68040

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000277 Hom.: 0

Bravo AF: 0.000733

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

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	-0.92
CADD	Benign	0.58
DANN	Benign	0.47
PhyloP100		-0.91
Mutation Taster		=100/0	polymorphism

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: rs182303293; hg19: chr10-127477341;