rs2281955

Variant names:

• chr10-125796048-C-G
• rs2281955
• NM_000375.3:c.561+55G>C

Your query was ambiguous. Multiple possible variants found:

• chr10-125796048-C-G
• chr10-125796048-C-T

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.561+55G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 1,534,740 control chromosomes in the GnomAD database, including 155,769 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14212 hom., cov: 32)
  • Exomes 𝑓: 0.45 (141557 hom.)
• Consequence: UROS NM_000375.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.63
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 10-125796048-C-G is Benign according to our data. Variant chr10-125796048-C-G is described in ClinVar as Benign. ClinVar VariationId is 1257905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UROS	NM_000375.3	c.561+55G>C		intron_variant	Intron 8 of 9	ENST00000368797.10	NP_000366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UROS	ENST00000368797.10	c.561+55G>C		intron_variant	Intron 8 of 9	1	NM_000375.3	ENSP00000357787.4

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65181 AN: 151894 Hom.: 14196 Cov.: 32

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.538

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.428

GnomAD4 exome AF: 0.449 AC: 620885 AN: 1382728 Hom.: 141557 AF XY: 0.449 AC XY: 310876 AN XY: 692628

African (AFR) AF: 0.425 AC: 13504 AN: 31790

American (AMR) AF: 0.248 AC: 11083 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 9990 AN: 25646

East Asian (EAS) AF: 0.306 AC: 12050 AN: 39320

South Asian (SAS) AF: 0.424 AC: 35879 AN: 84696

European-Finnish (FIN) AF: 0.427 AC: 22775 AN: 53352

Middle Eastern (MID) AF: 0.336 AC: 1642 AN: 4888

European-Non Finnish (NFE) AF: 0.470 AC: 489202 AN: 1040714

Other (OTH) AF: 0.429 AC: 24760 AN: 57698

GnomAD4 genome AF: 0.429 AC: 65227 AN: 152012 Hom.: 14212 Cov.: 32 AF XY: 0.423 AC XY: 31452 AN XY: 74286

African (AFR) AF: 0.427 AC: 17703 AN: 41446

American (AMR) AF: 0.334 AC: 5096 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1354 AN: 3472

East Asian (EAS) AF: 0.294 AC: 1516 AN: 5154

South Asian (SAS) AF: 0.425 AC: 2044 AN: 4810

European-Finnish (FIN) AF: 0.429 AC: 4535 AN: 10560

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.463 AC: 31492 AN: 67978

Other (OTH) AF: 0.430 AC: 906 AN: 2106

Alfa AF: 0.447 Hom.: 1813

Bravo AF: 0.419

Asia WGS AF: 0.372 AC: 1294 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.23
DANN	Benign	0.50
PhyloP100		-1.6
PromoterAI		-0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2281955; hg19: chr10-127484617; COSMIC: COSV64229854; COSMIC: COSV64229854;