rs1671809392

Variant names:

• chr1-225920564-G-A
• rs1671809392
• NM_013328.4:c.854C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-225920564-G-A
• chr1-225920564-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_013328.4(PYCR2):​c.854C>T​(p.Thr285Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,457,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PYCR2 NM_013328.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.59
• Publications: 0 publications found

Genes affected

PYCR2 (HGNC:30262): (pyrroline-5-carboxylate reductase 2) This gene belongs to the pyrroline-5-carboxylate reductase family. The encoded mitochondrial protein catalyzes the conversion of pyrroline-5-carboxylate to proline, which is the last step in proline biosynthesis. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Nov 2012]

PYCR2 Gene-Disease associations (from GenCC):

• hypomyelinating leukodystrophy 10

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae)
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000255835 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.94826 (below the threshold of 3.09). Trascript score misZ: 0.76229 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive primary microcephaly, hypomyelinating leukodystrophy 10.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYCR2	NM_013328.4	c.854C>T	p.Thr285Ile	missense_variant	Exon 7 of 7	ENST00000343818.11	NP_037460.2
PYCR2	NM_001271681.2	c.632C>T	p.Thr211Ile	missense_variant	Exon 6 of 6		NP_001258610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYCR2	ENST00000343818.11	c.854C>T	p.Thr285Ile	missense_variant	Exon 7 of 7	1	NM_013328.4	ENSP00000342502.6
ENSG00000255835	ENST00000432920.2	c.575+644C>T		intron_variant	Intron 5 of 7	2		ENSP00000414068.2
PYCR2	ENST00000612039.4	c.632C>T	p.Thr211Ile	missense_variant	Exon 6 of 6	3		ENSP00000478165.1
PYCR2	ENST00000478402.5	n.2463C>T		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1457656 Hom.: 0 Cov.: 32 AF XY: 0.00000689 AC XY: 5 AN XY: 725456

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1108252

Other (OTH) AF: 0.00 AC: 0 AN: 60244

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.854C>T (p.T285I) alteration is located in exon 7 (coding exon 7) of the PYCR2 gene. This alteration results from a C to T substitution at nucleotide position 854, causing the threonine (T) at amino acid position 285 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.2	.;.;M
PhyloP100		9.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.3	.;.;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	.;.;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.64
MVP		0.97
MPC		1.0
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.81
Mutation Taster		=25/75	disease causing

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: rs1671809392; hg19: chr1-226108264;