1-18876276-T-C

Variant names:

• chr1-18876276-T-C
• rs7550822
• NM_003748.4:c.1338+39A>G

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0870
• Publications: 7 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.1338+39A>G		intron	N/A	NP_003739.2
	ALDH4A1	NM_170726.3		c.1338+39A>G		intron	N/A	NP_733844.1
	ALDH4A1	NM_001319218.2		c.1186-773A>G		intron	N/A	NP_001306147.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH4A1	ENST00000375341.8	TSL:1 MANE Select	c.1338+39A>G		intron	N/A	ENSP00000364490.3
	ALDH4A1	ENST00000290597.9	TSL:1	c.1338+39A>G		intron	N/A	ENSP00000290597.5
	ALDH4A1	ENST00000538839.5	TSL:1	c.1186-773A>G		intron	N/A	ENSP00000446071.1

Frequencies

GnomAD3 genomes AF: 0.922 AC: 140185 AN: 152094 Hom.: 65159 Cov.: 32

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

GnomAD2 exomes AF: 0.965 AC: 240390 AN: 249040 AF XY: 0.969

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 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

African (AFR) AF: 0.772 AC: 25824 AN: 33430

American (AMR) AF: 0.974 AC: 43525 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.968 AC: 25267 AN: 26092

East Asian (EAS) AF: 1.00 AC: 39661 AN: 39662

South Asian (SAS) AF: 0.983 AC: 84666 AN: 86146

European-Finnish (FIN) AF: 0.973 AC: 50291 AN: 51678

Middle Eastern (MID) AF: 0.932 AC: 5365 AN: 5754

European-Non Finnish (NFE) AF: 0.981 AC: 1089177 AN: 1110816

Other (OTH) AF: 0.964 AC: 58141 AN: 60312

GnomAD4 genome AF: 0.922 AC: 140271 AN: 152212 Hom.: 65191 Cov.: 32 AF XY: 0.924 AC XY: 68780 AN XY: 74430

African (AFR) AF: 0.778 AC: 32279 AN: 41482

American (AMR) AF: 0.957 AC: 14634 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.960 AC: 3334 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5167 AN: 5168

South Asian (SAS) AF: 0.981 AC: 4730 AN: 4820

European-Finnish (FIN) AF: 0.977 AC: 10373 AN: 10622

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.979 AC: 66589 AN: 68032

Other (OTH) AF: 0.936 AC: 1980 AN: 2116

Alfa AF: 0.954 Hom.: 12389

Bravo AF: 0.913

Asia WGS AF: 0.975 AC: 3390 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	-0.94
CADD	Benign	0.92
DANN	Benign	0.70
PhyloP100		-0.087
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs7550822; hg19: chr1-19202770;