rs2870983

Variant names:

• chr22-18918329-C-A
• rs2870983
• NM_016335.6:c.1414G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. 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. 15/20 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 Benign.

• 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
• Publications: 0 publications found

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]

PRODH Gene-Disease associations (from GenCC):

• hyperprolinemia type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000283809 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.061892837).

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11	c.1414G>T	p.Ala472Ser	missense_variant	Exon 11 of 14	1	NM_016335.6	ENSP00000349577.6
ENSG00000283809	ENST00000638240.1	c.513+7301C>A		intron_variant	Intron 4 of 5	5		ENSP00000492446.1

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

African (AFR) AF: 0.00 AC: 0 AN: 6258

American (AMR) AF: 0.00 AC: 0 AN: 6566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4606

East Asian (EAS) AF: 0.00 AC: 0 AN: 18546

South Asian (SAS) AF: 0.00 AC: 0 AN: 13630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 780

European-Non Finnish (NFE) AF: 0.0000136 AC: 1 AN: 73362

Other (OTH) AF: 0.00 AC: 0 AN: 8528

GnomAD4 genome Cov.: 5

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
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
PhyloP100		0.11
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
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs2870983; hg19: chr22-18905842;