10-125788966-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PM1 PM2 BP4_Strong BP6_Moderate BS1

The NM_000375.3(UROS):c.700G>A(p.Ala234Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,611,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: UROS NM_000375.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.295

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 Likely_benign. Variant got -6 ACMG points.

• PM1: In a chain Uroporphyrinogen-III synthase (size 264) in uniprot entity HEM4_HUMAN there are 25 pathogenic changes around while only 9 benign (74%) in NM_000375.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009634316).
• BP6: Variant 10-125788966-C-T is Benign according to our data. Variant chr10-125788966-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 745650.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000631 (96/152250) while in subpopulation AFR AF= 0.00183 (76/41558). AF 95% confidence interval is 0.0015. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UROS	NM_000375.3	c.700G>A	p.Ala234Thr	missense_variant	10/10	ENST00000368797.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UROS	ENST00000368797.10	c.700G>A	p.Ala234Thr	missense_variant	10/10	1	NM_000375.3	P1

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000278 AC: 67 AN: 240768 Hom.: 0 AF XY: 0.000220 AC XY: 29 AN XY: 131680

Gnomad AFR exome AF: 0.00205

Gnomad AMR exome AF: 0.0000584

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00151

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000560

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000125 AC: 182 AN: 1459506 Hom.: 0 Cov.: 30 AF XY: 0.000129 AC XY: 94 AN XY: 725942

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.000706

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000630

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000631 AC: 96 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000564 AC XY: 42 AN XY: 74432

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000106 Hom.: 0

Bravo AF: 0.000672

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000314 AC: 38

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Apr 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T;T;T;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.043	N
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.0096	T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.76	N;N;N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.38	N;.;N;.;.
REVEL	Benign	0.15
Sift	Benign	0.28	T;.;T;.;.
Sift4G	Benign	0.47	T;.;T;.;.
Polyphen		0.27	B;B;B;.;.
Vest4		0.14
MVP		0.78
MPC		0.086
ClinPred		0.0079	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.073
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs143947596; hg19: chr10-127477535; COSMIC: COSV64230092; COSMIC: COSV64230092;