NM_000375.3:c.738C>T

Variant names:

• chr10-125788928-G-A
• rs146070712
• NM_000375.3:c.738C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS1

The NM_000375.3(UROS):​c.738C>T​(p.Pro246Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,609,648 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: UROS NM_000375.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.900
• Publications: 1 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, G2P, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 10-125788928-G-A is Benign according to our data. Variant chr10-125788928-G-A is described in ClinVar as Benign. ClinVar VariationId is 2865079.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.9 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000578 (88/152364) while in subpopulation AFR AF = 0.00209 (87/41594). AF 95% confidence interval is 0.00174. There are 1 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.738C>T	p.Pro246Pro	synonymous	Exon 10 of 10	NP_000366.1	A0A0S2Z4T8
	UROS	NM_001324036.2		c.819C>T	p.Pro273Pro	synonymous	Exon 11 of 11	NP_001310965.1	A0A3B3ISM6
	UROS	NM_001324037.2		c.738C>T	p.Pro246Pro	synonymous	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.738C>T	p.Pro246Pro	synonymous	Exon 10 of 10	ENSP00000357787.4	P10746
	UROS	ENST00000368786.5	TSL:1	c.738C>T	p.Pro246Pro	synonymous	Exon 9 of 9	ENSP00000357775.1	P10746
	UROS	ENST00000940865.1		c.918C>T	p.Pro306Pro	synonymous	Exon 11 of 11	ENSP00000610924.1

Frequencies

GnomAD3 genomes AF: 0.000558 AC: 85 AN: 152246 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000134 AC: 32 AN: 238662 AF XY: 0.0000924

Gnomad AFR exome AF: 0.00200

Gnomad AMR exome AF: 0.0000595

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000618 AC: 90 AN: 1457284 Hom.: 0 Cov.: 30 AF XY: 0.0000511 AC XY: 37 AN XY: 724642

African (AFR) AF: 0.00230 AC: 77 AN: 33470

American (AMR) AF: 0.000113 AC: 5 AN: 44124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25914

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.00 AC: 0 AN: 85302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111128

Other (OTH) AF: 0.000116 AC: 7 AN: 60198

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152364 Hom.: 1 Cov.: 33 AF XY: 0.000591 AC XY: 44 AN XY: 74510

African (AFR) AF: 0.00209 AC: 87 AN: 41594

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000461 Hom.: 1

Bravo AF: 0.000752

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	13
DANN	Benign	0.78
PhyloP100		0.90
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: rs146070712; hg19: chr10-127477497;