10-125815059-ACA-GCC

Variant names:

• chr10-125815059-ACA-GCC
• NM_000375.3:c.217_219delTGTinsGGC
• UROS p.Cys73Gly

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM5

The NM_000375.3(UROS):​c.217_219delTGTinsGGC​(p.Cys73Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C73R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UROS NM_000375.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.72
• Publications: 0 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-125815061-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 3750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.217_219delTGTinsGGC	p.Cys73Gly	missense	N/A	NP_000366.1	A0A0S2Z4T8
	UROS	NM_001324036.2		c.217_219delTGTinsGGC	p.Cys73Gly	missense	N/A	NP_001310965.1	A0A3B3ISM6
	UROS	NM_001324037.2		c.217_219delTGTinsGGC	p.Cys73Gly	missense	N/A	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.217_219delTGTinsGGC	p.Cys73Gly	missense	N/A	ENSP00000357787.4	P10746
	UROS	ENST00000368786.5	TSL:1	c.217_219delTGTinsGGC	p.Cys73Gly	missense	N/A	ENSP00000357775.1	P10746
	UROS	ENST00000940865.1		c.217_219delTGTinsGGC	p.Cys73Gly	missense	N/A	ENSP00000610924.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr10-127503628;