ENST00000337943.9:c.924G>T

Variant names:

• chr17-81932907-C-A
• rs201670221
• ENST00000337943.9:c.924G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000337943.9(PYCR1):​c.924G>T​(p.Gln308His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,611,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: PYCR1 ENST00000337943.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.145
• Publications: 0 publications found

Genes affected

PYCR1 (HGNC:9721): (pyrroline-5-carboxylate reductase 1) This gene encodes an enzyme that catalyzes the NAD(P)H-dependent conversion of pyrroline-5-carboxylate to proline. This enzyme may also play a physiologic role in the generation of NADP(+) in some cell types. The protein forms a homopolymer and localizes to the mitochondrion. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

PYCR1 Gene-Disease associations (from GenCC):

• autosomal recessive cutis laxa type 2B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• PYCR1-related de Barsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics
• geroderma osteodysplastica

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PYCR1-AS1 (HGNC:56889):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.033626437).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000337943.9. 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
	PYCR1	NM_006907.4	MANE Select	c.*307G>T		3_prime_UTR	Exon 7 of 7	NP_008838.2
	PYCR1	NM_153824.3		c.924G>T	p.Gln308His	missense	Exon 8 of 8	NP_722546.1	P32322-2
	PYCR1	NM_001282281.2		c.*307G>T		3_prime_UTR	Exon 8 of 8	NP_001269210.1	P32322-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYCR1	ENST00000337943.9	TSL:1	c.924G>T	p.Gln308His	missense	Exon 8 of 8	ENSP00000336579.5	P32322-2
	PYCR1	ENST00000329875.13	TSL:1 MANE Select	c.*307G>T		3_prime_UTR	Exon 7 of 7	ENSP00000328858.8	P32322-1
	PYCR1	ENST00000619204.4	TSL:1	c.*307G>T		3_prime_UTR	Exon 8 of 8	ENSP00000479793.1	P32322-1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000175 AC: 43 AN: 245412 AF XY: 0.000233

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000585

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000482

Gnomad NFE exome AF: 0.000253

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000179 AC: 261 AN: 1459260 Hom.: 0 Cov.: 30 AF XY: 0.000207 AC XY: 150 AN XY: 725660

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.0000674 AC: 3 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

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

South Asian (SAS) AF: 0.000431 AC: 37 AN: 85764

European-Finnish (FIN) AF: 0.0000953 AC: 5 AN: 52448

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.000184 AC: 205 AN: 1111296

Other (OTH) AF: 0.000149 AC: 9 AN: 60294

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000174 AC XY: 13 AN XY: 74508

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.000261 AC: 4 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68038

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000167 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000223 AC: 27

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive cutis laxa type 2B;C3280799:PYCR1-related de Barsy syndrome (1)
-	1	-	Cutis laxa (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.7
DANN	Benign	0.79
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.14
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.094
Sift	Benign	0.082	T
Sift4G	Uncertain	0.044	D
Vest4		0.090
MutPred		0.24		Gain of helix (P = 0.0022)
MVP		0.20
ClinPred		0.0098	T
GERP RS		1.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Mutation Taster		=99/1	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: rs201670221; hg19: chr17-79890783;