rs1140477

Variant names:

• chr1-18871920-G-A
• rs1140477
• NM_003748.4:c.*925C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-18871920-G-A
• chr1-18871920-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003748.4(ALDH4A1):​c.*925C>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 0.252 in 152,162 control chromosomes in the GnomAD database, including 4,967 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4962 hom., cov: 34)
  • Exomes 𝑓: 0.24 (5 hom.)
• Consequence: ALDH4A1 NM_003748.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.589
• Publications: 4 publications found

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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics, ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-18871920-G-A is Benign according to our data. Variant chr1-18871920-G-A is described in ClinVar as Benign. ClinVar VariationId is 294341.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH4A1	NM_003748.4	MANE Select	c.*925C>T		3_prime_UTR	Exon 15 of 15	NP_003739.2
	ALDH4A1	NM_001319218.2		c.*925C>T		3_prime_UTR	Exon 14 of 14	NP_001306147.1	P30038-3
	ALDH4A1	NM_001161504.2		c.*925C>T		3_prime_UTR	Exon 15 of 15	NP_001154976.1	P30038-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH4A1	ENST00000375341.8	TSL:1 MANE Select	c.*925C>T		3_prime_UTR	Exon 15 of 15	ENSP00000364490.3	P30038-1
	ALDH4A1	ENST00000538839.5	TSL:1	c.*925C>T		3_prime_UTR	Exon 14 of 14	ENSP00000446071.1	P30038-3
	ALDH4A1	ENST00000290597.9	TSL:1	c.*42-130C>T		intron	N/A	ENSP00000290597.5	P30038-1

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38234 AN: 151940 Hom.: 4959 Cov.: 34

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.290

Gnomad EAS AF: 0.0346

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.257

GnomAD4 exome AF: 0.240 AC: 25 AN: 104 Hom.: 5 Cov.: 0 AF XY: 0.263 AC XY: 20 AN XY: 76

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 1.00 AC: 2 AN: 2

European-Finnish (FIN) AF: 0.143 AC: 2 AN: 14

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.263 AC: 20 AN: 76

Other (OTH) AF: 0.167 AC: 1 AN: 6

GnomAD4 genome AF: 0.252 AC: 38260 AN: 152058 Hom.: 4962 Cov.: 34 AF XY: 0.245 AC XY: 18230 AN XY: 74312

African (AFR) AF: 0.252 AC: 10437 AN: 41484

American (AMR) AF: 0.237 AC: 3625 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 1004 AN: 3468

East Asian (EAS) AF: 0.0347 AC: 180 AN: 5186

South Asian (SAS) AF: 0.159 AC: 769 AN: 4828

European-Finnish (FIN) AF: 0.241 AC: 2544 AN: 10570

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.276 AC: 18738 AN: 67930

Other (OTH) AF: 0.259 AC: 546 AN: 2112

Alfa AF: 0.259 Hom.: 6280

Bravo AF: 0.255

Asia WGS AF: 0.116 AC: 408 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hyperprolinemia type 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.5
DANN	Benign	0.42
PhyloP100		0.59
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1140477; hg19: chr1-19198414;