Genetic Variant NM_003748.4:c.*712C>T (chr1-18872133-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003748.4(ALDH4A1):c.*712C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 152,444 control chromosomes in the GnomAD database, including 4,995 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 4988 hom., cov: 35)

Exomes 𝑓: 0.20 ( 7 hom. )

Consequence

ALDH4A1
NM_003748.4 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.00900

Publications

3 publications found

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]

ALDH4A1 Gene-Disease associations (from GenCC):

hyperprolinemia type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ALDH4A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 1-18872133-G-A is Benign according to our data. Variant chr1-18872133-G-A is described in ClinVar as Benign. ClinVar VariationId is 294346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003748.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ALDH4A1	NM_003748.4	MANE Select	c.*712C>T	3_prime_UTR	Exon 15 of 15	NP_003739.2
ALDH4A1	NM_001319218.2		c.*712C>T	3_prime_UTR	Exon 14 of 14	NP_001306147.1	P30038-3
ALDH4A1	NM_001161504.2		c.*712C>T	3_prime_UTR	Exon 15 of 15	NP_001154976.1	P30038-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ALDH4A1	ENST00000375341.8	TSL:1 MANE Select	c.*712C>T	3_prime_UTR	Exon 15 of 15	ENSP00000364490.3	P30038-1
ALDH4A1	ENST00000538839.5	TSL:1	c.*712C>T	3_prime_UTR	Exon 14 of 14	ENSP00000446071.1	P30038-3
ALDH4A1	ENST00000290597.9	TSL:1	c.*42-343C>T	intron	N/A	ENSP00000290597.5	P30038-1

Frequencies

GnomAD3 genomes

AF:

0.251

AC:

38155

AN:

152102

Hom.:

4985

Cov.:

show subpopulations

Gnomad AFR

AF:

0.246

Gnomad AMI

AF:

0.363

Gnomad AMR

AF:

0.238

Gnomad ASJ

AF:

0.290

Gnomad EAS

AF:

0.0348

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.247

Gnomad MID

AF:

0.297

Gnomad NFE

AF:

0.276

Gnomad OTH

AF:

0.256

GnomAD4 exome

AF:

0.201

AC:

AN:

224

Hom.:

Cov.:

AF XY:

0.207

AC XY:

AN XY:

174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.250

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.125

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.225

AC:

AN:

182

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.251

AC:

38173

AN:

152220

Hom.:

4988

Cov.:

AF XY:

0.245

AC XY:

18239

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.246

AC:

10226

AN:

41530

American (AMR)

AF:

0.238

AC:

3643

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.290

AC:

1006

AN:

3472

East Asian (EAS)

AF:

0.0348

AC:

180

AN:

5166

South Asian (SAS)

AF:

0.159

AC:

768

AN:

4826

European-Finnish (FIN)

AF:

0.247

AC:

2618

AN:

10606

Middle Eastern (MID)

AF:

0.303

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.276

AC:

18778

AN:

68006

Other (OTH)

AF:

0.253

AC:

534

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1530

3059

4589

6118

7648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

398

796

1194

1592

1990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.264

Hom.:

14830

Bravo

AF:

0.253

Asia WGS

AF:

0.107

AC:

376

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyperprolinemia type 2 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

3.6

(source)

DANN

Benign

0.72

PhyloP100

-0.0090

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over