Genetic Variant NM_003748.4:c.*1275A>C (chr1-18871570-T-G) – 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.*1275A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 152,262 control chromosomes in the GnomAD database, including 4,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 4699 hom., cov: 33)

Exomes 𝑓: 0.25 ( 12 hom. )

Consequence

ALDH4A1
NM_003748.4 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.922

Publications

5 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=-0.84).

BP6

Variant 1-18871570-T-G is Benign according to our data. Variant chr1-18871570-T-G is described in ClinVar as Benign. ClinVar VariationId is 294333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.274 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.*1275A>C	3_prime_UTR	Exon 15 of 15	NP_003739.2
ALDH4A1	NM_170726.3		c.*262A>C	3_prime_UTR	Exon 16 of 16	NP_733844.1	P30038-1
ALDH4A1	NM_001319218.2		c.*1275A>C	3_prime_UTR	Exon 14 of 14	NP_001306147.1	P30038-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ALDH4A1	ENST00000375341.8	TSL:1 MANE Select	c.*1275A>C	3_prime_UTR	Exon 15 of 15	ENSP00000364490.3	P30038-1
ALDH4A1	ENST00000290597.9	TSL:1	c.*262A>C	3_prime_UTR	Exon 16 of 16	ENSP00000290597.5	P30038-1
ALDH4A1	ENST00000538839.5	TSL:1	c.*1275A>C	3_prime_UTR	Exon 14 of 14	ENSP00000446071.1	P30038-3

Frequencies

GnomAD3 genomes

AF:

0.242

AC:

36757

AN:

151886

Hom.:

4696

Cov.:

show subpopulations

Gnomad AFR

AF:

0.216

Gnomad AMI

AF:

0.362

Gnomad AMR

AF:

0.234

Gnomad ASJ

AF:

0.284

Gnomad EAS

AF:

0.0350

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.244

Gnomad MID

AF:

0.304

Gnomad NFE

AF:

0.277

Gnomad OTH

AF:

0.250

GnomAD4 exome

AF:

0.254

AC:

AN:

256

Hom.:

Cov.:

AF XY:

0.250

AC XY:

AN XY:

204

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.389

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.267

AC:

AN:

202

Other (OTH)

AF:

0.250

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.242

AC:

36782

AN:

152006

Hom.:

4699

Cov.:

AF XY:

0.236

AC XY:

17541

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.216

AC:

8941

AN:

41462

American (AMR)

AF:

0.234

AC:

3571

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.284

AC:

987

AN:

3472

East Asian (EAS)

AF:

0.0350

AC:

181

AN:

5166

South Asian (SAS)

AF:

0.159

AC:

767

AN:

4818

European-Finnish (FIN)

AF:

0.244

AC:

2566

AN:

10534

Middle Eastern (MID)

AF:

0.310

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.277

AC:

18819

AN:

67968

Other (OTH)

AF:

0.251

AC:

530

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1461

2922

4383

5844

7305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

386

772

1158

1544

1930

<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:

0.266

Hom.:

19318

Bravo

AF:

0.243

Asia WGS

AF:

0.114

AC:

400

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

-0.84

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

0.92

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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