rs2870983

Positions:

• chr22-18918329-C-A
• chr22-18918329-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM5 BP4_Strong

The NM_016335.6(PRODH):​c.1414G>T​(p.Ala472Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. 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. A472T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 5)
  • Exomes 𝑓: 0.0000071 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.110

Genes affected

PRODH (HGNC:9453): (proline dehydrogenase 1) This gene encodes a mitochondrial protein that catalyzes the first step in proline degradation. Mutations in this gene are associated with hyperprolinemia type 1 and susceptibility to schizophrenia 4 (SCZD4). This gene is located on chromosome 22q11.21, a region which has also been associated with the contiguous gene deletion syndromes, DiGeorge and CATCH22. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.061892837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRODH	NM_016335.6	c.1414G>T	p.Ala472Ser	missense_variant	11/14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2	c.1090G>T	p.Ala364Ser	missense_variant	11/14		NP_001182155.2
PRODH	NM_001368250.2	c.1090G>T	p.Ala364Ser	missense_variant	11/14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11	c.1414G>T	p.Ala472Ser	missense_variant	11/14	1	NM_016335.6	ENSP00000349577	P3

Frequencies

GnomAD3 genomes Cov.: 5

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000712 AC: 1 AN: 140520 Hom.: 0 Cov.: 0 AF XY: 0.0000135 AC XY: 1 AN XY: 74102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000136

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 5

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.8
DANN	Benign	0.85
DEOGEN2	Benign	0.016	T;.;.;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.38	T;.;T;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.062	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.31	.;N;N;N
REVEL	Benign	0.021
Sift	Benign	0.68	.;T;T;T
Sift4G	Benign	0.72	T;T;T;T
Polyphen		0.24	.;B;B;.
Vest4		0.26
MutPred		0.30		Gain of disorder (P = 0.0669);.;.;Gain of disorder (P = 0.0669);
MVP		0.014
MPC		0.27
ClinPred		0.21	T
GERP RS		0.86
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-18905842;