rs10901431

Positions:

• chr10-125785806-T-C
• chr10-125785806-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000622016.4(UROS):​c.274A>G​(p.Met92Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 152,206 control chromosomes in the GnomAD database, including 16,580 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/7 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (16579 hom., cov: 33)
  • Exomes 𝑓: 0.42 (1 hom.)
• Consequence: UROS ENST00000622016.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.01

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.0616264E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UROS	XM_017016612.3	c.694A>G	p.Met232Val	missense_variant	10/10		XP_016872101.1
UROS	XM_011540127.3	c.661-546A>G		intron_variant			XP_011538429.1
UROS	NR_136677.2	n.950A>G		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UROS	ENST00000622016.4	c.274A>G	p.Met92Val	missense_variant	4/4	5		ENSP00000483041
UROS	ENST00000616800.4	c.161-546A>G		intron_variant		5		ENSP00000482520

Frequencies

GnomAD3 genomes AF: 0.462 AC: 70265 AN: 152064 Hom.: 16553 Cov.: 33

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.539

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.452

GnomAD4 exome AF: 0.417 AC: 10 AN: 24 Hom.: 1 Cov.: 0 AF XY: 0.438 AC XY: 7 AN XY: 16

Gnomad4 EAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.462 AC: 70339 AN: 152182 Hom.: 16579 Cov.: 33 AF XY: 0.456 AC XY: 33951 AN XY: 74412

Gnomad4 AFR AF: 0.528

Gnomad4 AMR AF: 0.344

Gnomad4 ASJ AF: 0.394

Gnomad4 EAS AF: 0.321

Gnomad4 SAS AF: 0.455

Gnomad4 FIN AF: 0.429

Gnomad4 NFE AF: 0.468

Gnomad4 OTH AF: 0.455

Alfa AF: 0.454 Hom.: 15803

Bravo AF: 0.456

TwinsUK AF: 0.463 AC: 1716

ALSPAC AF: 0.477 AC: 1840

Asia WGS AF: 0.400 AC: 1393 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.95	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.23
DANN	Benign	0.73
DEOGEN2	Benign	0.023	T
FATHMM_MKL	Benign	0.00058	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.00051	T
Sift4G	Benign	0.071	T
MVP		0.37
GERP RS		-0.68

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10901431; hg19: chr10-127474375;