GeneBe

rs370707645

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2BP4_StrongBP6_ModerateBP7BS1

The NM_003748.4(ALDH4A1):​c.1272C>T​(p.Ser424Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,613,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

ALDH4A1
NM_003748.4 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -10.4
Variant links:
Genes affected
ALDH4A1 (HGNC:406): (aldehyde dehydrogenase 4 family member A1) This protein belongs to the aldehyde dehydrogenase family of proteins. This enzyme is a mitochondrial matrix NAD-dependent dehydrogenase which catalyzes the second step of the proline degradation pathway, converting pyrroline-5-carboxylate to glutamate. Deficiency of this enzyme is associated with type II hyperprolinemia, an autosomal recessive disorder characterized by accumulation of delta-1-pyrroline-5-carboxylate (P5C) and proline. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jun 2009]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.68).
BP6
Variant 1-18876381-G-A is Benign according to our data. Variant chr1-18876381-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 471327.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=-10.4 with no splicing effect.
BS1
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000155 (227/1461442) while in subpopulation AMR AF= 0.000447 (20/44714). AF 95% confidence interval is 0.000296. There are 0 homozygotes in gnomad4_exome. There are 112 alleles in male gnomad4_exome subpopulation. Median coverage is 42. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ALDH4A1NM_003748.4 linkuse as main transcriptc.1272C>T p.Ser424Ser synonymous_variant 12/15 ENST00000375341.8 NP_003739.2 P30038-1A0A024RAC7
ALDH4A1NM_170726.3 linkuse as main transcriptc.1272C>T p.Ser424Ser synonymous_variant 12/16 NP_733844.1 P30038-1A0A024RAC7
ALDH4A1NM_001161504.2 linkuse as main transcriptc.1092C>T p.Ser364Ser synonymous_variant 12/15 NP_001154976.1 P30038-2
ALDH4A1NM_001319218.2 linkuse as main transcriptc.1185+827C>T intron_variant NP_001306147.1 P30038-3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ALDH4A1ENST00000375341.8 linkuse as main transcriptc.1272C>T p.Ser424Ser synonymous_variant 12/151 NM_003748.4 ENSP00000364490.3 P30038-1
ALDH4A1ENST00000290597.9 linkuse as main transcriptc.1272C>T p.Ser424Ser synonymous_variant 12/161 ENSP00000290597.5 P30038-1
ALDH4A1ENST00000538839.5 linkuse as main transcriptc.1185+827C>T intron_variant 1 ENSP00000446071.1 P30038-3
ALDH4A1ENST00000538309.5 linkuse as main transcriptc.1092C>T p.Ser364Ser synonymous_variant 12/152 ENSP00000442988.1 P30038-2

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152172
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000163
AC:
41
AN:
250860
Hom.:
0
AF XY:
0.000147
AC XY:
20
AN XY:
135618
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.000376
Gnomad ASJ exome
AF:
0.000199
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000185
Gnomad OTH exome
AF:
0.000654
GnomAD4 exome
AF:
0.000155
AC:
227
AN:
1461442
Hom.:
0
Cov.:
42
AF XY:
0.000154
AC XY:
112
AN XY:
727026
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.000447
Gnomad4 ASJ exome
AF:
0.000306
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.0000376
Gnomad4 NFE exome
AF:
0.000162
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152172
Hom.:
0
Cov.:
33
AF XY:
0.0000673
AC XY:
5
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000124
Hom.:
0
Bravo
AF:
0.000110
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.000273
EpiControl
AF:
0.000415

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hyperprolinemia type 2 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 15, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.68
CADD
Benign
0.023
DANN
Benign
0.82

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs370707645; hg19: chr1-19202875; COSMIC: COSV99312415; API