1-18877467-C-T

Variant names:

• chr1-18877467-C-T
• rs41310410
• NM_003748.4:c.1086G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003748.4(ALDH4A1):​c.1086G>A​(p.Pro362Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.031 in 1,594,862 control chromosomes in the GnomAD database, including 865 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P362P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.024 (68 hom., cov: 32)
  • Exomes 𝑓: 0.032 (797 hom.)
• Consequence: ALDH4A1 NM_003748.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.104
• Publications: 5 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: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 1-18877467-C-T is Benign according to our data. Variant chr1-18877467-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 471326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.104 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0242 (3686/152354) while in subpopulation NFE AF = 0.0336 (2283/68024). AF 95% confidence interval is 0.0324. There are 68 homozygotes in GnomAd4. There are 1819 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 68 AR gene

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.1086G>A	p.Pro362Pro	synonymous	Exon 10 of 15	NP_003739.2
	ALDH4A1	NM_170726.3		c.1086G>A	p.Pro362Pro	synonymous	Exon 10 of 16	NP_733844.1	P30038-1
	ALDH4A1	NM_001319218.2		c.1086G>A	p.Pro362Pro	synonymous	Exon 10 of 14	NP_001306147.1	P30038-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH4A1	ENST00000375341.8	TSL:1 MANE Select	c.1086G>A	p.Pro362Pro	synonymous	Exon 10 of 15	ENSP00000364490.3	P30038-1
	ALDH4A1	ENST00000290597.9	TSL:1	c.1086G>A	p.Pro362Pro	synonymous	Exon 10 of 16	ENSP00000290597.5	P30038-1
	ALDH4A1	ENST00000538839.5	TSL:1	c.1086G>A	p.Pro362Pro	synonymous	Exon 10 of 14	ENSP00000446071.1	P30038-3

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3684 AN: 152236 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.00629

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0289

Gnomad ASJ AF: 0.0628

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.0293

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0336

Gnomad OTH AF: 0.0297

GnomAD2 exomes AF: 0.0248 AC: 5426 AN: 219070 AF XY: 0.0244

Gnomad AFR exome AF: 0.00538

Gnomad AMR exome AF: 0.0167

Gnomad ASJ exome AF: 0.0491

Gnomad EAS exome AF: 0.0000605

Gnomad FIN exome AF: 0.0295

Gnomad NFE exome AF: 0.0360

Gnomad OTH exome AF: 0.0295

GnomAD4 exome AF: 0.0317 AC: 45680 AN: 1442508 Hom.: 797 Cov.: 33 AF XY: 0.0310 AC XY: 22211 AN XY: 715770

African (AFR) AF: 0.00512 AC: 170 AN: 33186

American (AMR) AF: 0.0176 AC: 750 AN: 42538

Ashkenazi Jewish (ASJ) AF: 0.0517 AC: 1331 AN: 25746

East Asian (EAS) AF: 0.00 AC: 0 AN: 38982

South Asian (SAS) AF: 0.00605 AC: 505 AN: 83450

European-Finnish (FIN) AF: 0.0277 AC: 1407 AN: 50822

Middle Eastern (MID) AF: 0.0182 AC: 101 AN: 5544

European-Non Finnish (NFE) AF: 0.0361 AC: 39838 AN: 1102592

Other (OTH) AF: 0.0265 AC: 1578 AN: 59648

GnomAD4 genome AF: 0.0242 AC: 3686 AN: 152354 Hom.: 68 Cov.: 32 AF XY: 0.0244 AC XY: 1819 AN XY: 74496

African (AFR) AF: 0.00627 AC: 261 AN: 41598

American (AMR) AF: 0.0289 AC: 443 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 218 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00517 AC: 25 AN: 4832

European-Finnish (FIN) AF: 0.0293 AC: 311 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0336 AC: 2283 AN: 68024

Other (OTH) AF: 0.0294 AC: 62 AN: 2112

Alfa AF: 0.0313 Hom.: 201

Bravo AF: 0.0238

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.93
PhyloP100		-0.10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs41310410; hg19: chr1-19203961;