rs2281956

Variant names:

• chr10-125795974-G-C
• rs2281956
• NM_000375.3:c.561+129C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-125795974-G-C
• chr10-125795974-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000375.3(UROS):​c.561+129C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 832,988 control chromosomes in the GnomAD database, including 79,252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.43 (14207 hom., cov: 32)
  • Exomes 𝑓: 0.43 (65045 hom.)
• Consequence: UROS NM_000375.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0790
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-125795974-G-C is Benign according to our data. Variant chr10-125795974-G-C is described in ClinVar as Benign. ClinVar VariationId is 1265038.Status of the report is criteria_provided_single_submitter, 1 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+129C>G		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+129C>G		intron_variant	Intron 8 of 9	1	NM_000375.3	ENSP00000357787.4

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65134 AN: 151886 Hom.: 14192 Cov.: 32

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.538

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.414

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.425

GnomAD4 exome AF: 0.431 AC: 293678 AN: 680984 Hom.: 65045 AF XY: 0.432 AC XY: 157418 AN XY: 364206

African (AFR) AF: 0.425 AC: 7858 AN: 18476

American (AMR) AF: 0.246 AC: 10567 AN: 43024

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 8048 AN: 20758

East Asian (EAS) AF: 0.313 AC: 11178 AN: 35756

South Asian (SAS) AF: 0.414 AC: 28797 AN: 69538

European-Finnish (FIN) AF: 0.424 AC: 21995 AN: 51912

Middle Eastern (MID) AF: 0.339 AC: 884 AN: 2606

European-Non Finnish (NFE) AF: 0.469 AC: 189871 AN: 404548

Other (OTH) AF: 0.421 AC: 14480 AN: 34366

GnomAD4 genome AF: 0.429 AC: 65180 AN: 152004 Hom.: 14207 Cov.: 32 AF XY: 0.423 AC XY: 31414 AN XY: 74284

African (AFR) AF: 0.429 AC: 17758 AN: 41426

American (AMR) AF: 0.332 AC: 5073 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1350 AN: 3472

East Asian (EAS) AF: 0.290 AC: 1500 AN: 5164

South Asian (SAS) AF: 0.414 AC: 1994 AN: 4812

European-Finnish (FIN) AF: 0.429 AC: 4531 AN: 10558

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

European-Non Finnish (NFE) AF: 0.463 AC: 31491 AN: 67992

Other (OTH) AF: 0.428 AC: 903 AN: 2110

Alfa AF: 0.456 Hom.: 1929

Bravo AF: 0.420

Asia WGS AF: 0.367 AC: 1280 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.82
PhyloP100		0.079
PromoterAI		-0.027	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: rs2281956; hg19: chr10-127484543; COSMIC: COSV64229824; COSMIC: COSV64229824;