chr1-18876276-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003748.4(ALDH4A1):​c.1338+39A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.97 in 1,610,774 control chromosomes in the GnomAD database, including 759,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.92 ( 65191 hom., cov: 32)
Exomes 𝑓: 0.97 ( 693932 hom. )

Consequence

ALDH4A1
NM_003748.4 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0870
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.94).
BP6
Variant 1-18876276-T-C is Benign according to our data. Variant chr1-18876276-T-C is described in ClinVar as [Benign]. Clinvar id is 1188872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ALDH4A1NM_003748.4 linkuse as main transcriptc.1338+39A>G intron_variant ENST00000375341.8 NP_003739.2
ALDH4A1NM_001161504.2 linkuse as main transcriptc.1158+39A>G intron_variant NP_001154976.1
ALDH4A1NM_001319218.2 linkuse as main transcriptc.1186-773A>G intron_variant NP_001306147.1
ALDH4A1NM_170726.3 linkuse as main transcriptc.1338+39A>G intron_variant NP_733844.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ALDH4A1ENST00000375341.8 linkuse as main transcriptc.1338+39A>G intron_variant 1 NM_003748.4 ENSP00000364490 P1P30038-1
ALDH4A1ENST00000290597.9 linkuse as main transcriptc.1338+39A>G intron_variant 1 ENSP00000290597 P1P30038-1
ALDH4A1ENST00000538839.5 linkuse as main transcriptc.1186-773A>G intron_variant 1 ENSP00000446071 P30038-3
ALDH4A1ENST00000538309.5 linkuse as main transcriptc.1158+39A>G intron_variant 2 ENSP00000442988 P30038-2

Frequencies

GnomAD3 genomes
AF:
0.922
AC:
140185
AN:
152094
Hom.:
65159
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.778
Gnomad AMI
AF:
1.00
Gnomad AMR
AF:
0.957
Gnomad ASJ
AF:
0.960
Gnomad EAS
AF:
1.00
Gnomad SAS
AF:
0.981
Gnomad FIN
AF:
0.977
Gnomad MID
AF:
0.937
Gnomad NFE
AF:
0.979
Gnomad OTH
AF:
0.935
GnomAD3 exomes
AF:
0.965
AC:
240390
AN:
249040
Hom.:
116379
AF XY:
0.969
AC XY:
130578
AN XY:
134808
show subpopulations
Gnomad AFR exome
AF:
0.771
Gnomad AMR exome
AF:
0.976
Gnomad ASJ exome
AF:
0.971
Gnomad EAS exome
AF:
1.00
Gnomad SAS exome
AF:
0.984
Gnomad FIN exome
AF:
0.973
Gnomad NFE exome
AF:
0.978
Gnomad OTH exome
AF:
0.964
GnomAD4 exome
AF:
0.975
AC:
1421917
AN:
1458562
Hom.:
693932
Cov.:
33
AF XY:
0.976
AC XY:
707982
AN XY:
725710
show subpopulations
Gnomad4 AFR exome
AF:
0.772
Gnomad4 AMR exome
AF:
0.974
Gnomad4 ASJ exome
AF:
0.968
Gnomad4 EAS exome
AF:
1.00
Gnomad4 SAS exome
AF:
0.983
Gnomad4 FIN exome
AF:
0.973
Gnomad4 NFE exome
AF:
0.981
Gnomad4 OTH exome
AF:
0.964
GnomAD4 genome
AF:
0.922
AC:
140271
AN:
152212
Hom.:
65191
Cov.:
32
AF XY:
0.924
AC XY:
68780
AN XY:
74430
show subpopulations
Gnomad4 AFR
AF:
0.778
Gnomad4 AMR
AF:
0.957
Gnomad4 ASJ
AF:
0.960
Gnomad4 EAS
AF:
1.00
Gnomad4 SAS
AF:
0.981
Gnomad4 FIN
AF:
0.977
Gnomad4 NFE
AF:
0.979
Gnomad4 OTH
AF:
0.936
Alfa
AF:
0.954
Hom.:
12389
Bravo
AF:
0.913
Asia WGS
AF:
0.975
AC:
3390
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Hyperprolinemia type 2 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.94
CADD
Benign
0.92
DANN
Benign
0.70
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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: rs7550822; hg19: chr1-19202770; API