NM_000375.3:c.691G>T

Variant names:

• chr10-125788975-C-A
• rs780837512
• NM_000375.3:c.691G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000375.3(UROS):​c.691G>T​(p.Ala231Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: UROS NM_000375.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.53

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_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Uroporphyrinogen-III synthase (size 264) in uniprot entity HEM4_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000375.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UROS	NM_000375.3	c.691G>T	p.Ala231Ser	missense_variant	Exon 10 of 10	ENST00000368797.10	NP_000366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UROS	ENST00000368797.10	c.691G>T	p.Ala231Ser	missense_variant	Exon 10 of 10	1	NM_000375.3	ENSP00000357787.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74308

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;D;D;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	.;.;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.6	M;M;M;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.0	N;.;N;.;.
REVEL	Uncertain	0.60
Sift	Benign	0.097	T;.;T;.;.
Sift4G	Benign	0.079	T;.;T;.;.
Polyphen		1.0	D;D;D;.;.
Vest4		0.54
MutPred		0.70		Gain of glycosylation at A231 (P = 0.0489);Gain of glycosylation at A231 (P = 0.0489);Gain of glycosylation at A231 (P = 0.0489);.;Gain of glycosylation at A231 (P = 0.0489);
MVP		0.88
MPC		0.45
ClinPred		0.89	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.46
gMVP		0.56

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: rs780837512; hg19: chr10-127477544;