chr1-18876423-T-C

Variant names:

• chr1-18876423-T-C
• rs7550938
• NM_003748.4:c.1230A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003748.4(ALDH4A1):​c.1230A>G​(p.Ser410Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.695 in 1,608,858 control chromosomes in the GnomAD database, including 391,287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31993 hom., cov: 32)
  • Exomes 𝑓: 0.70 (359294 hom.)
• Consequence: ALDH4A1 NM_003748.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -6.07
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-18876423-T-C is Benign according to our data. Variant chr1-18876423-T-C is described in ClinVar as Benign. ClinVar VariationId is 294375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.74 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.1230A>G	p.Ser410Ser	synonymous	Exon 12 of 15	NP_003739.2
	ALDH4A1	NM_170726.3		c.1230A>G	p.Ser410Ser	synonymous	Exon 12 of 16	NP_733844.1	P30038-1
	ALDH4A1	NM_001161504.2		c.1050A>G	p.Ser350Ser	synonymous	Exon 12 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.1230A>G	p.Ser410Ser	synonymous	Exon 12 of 15	ENSP00000364490.3	P30038-1
	ALDH4A1	ENST00000290597.9	TSL:1	c.1230A>G	p.Ser410Ser	synonymous	Exon 12 of 16	ENSP00000290597.5	P30038-1
	ALDH4A1	ENST00000538839.5	TSL:1	c.1185+785A>G		intron	N/A	ENSP00000446071.1	P30038-3

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97343 AN: 151436 Hom.: 31974 Cov.: 32

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.679

Gnomad EAS AF: 0.722

Gnomad SAS AF: 0.748

Gnomad FIN AF: 0.650

Gnomad MID AF: 0.657

Gnomad NFE AF: 0.695

Gnomad OTH AF: 0.678

GnomAD2 exomes AF: 0.699 AC: 170871 AN: 244574 AF XY: 0.701

Gnomad AFR exome AF: 0.484

Gnomad AMR exome AF: 0.795

Gnomad ASJ exome AF: 0.689

Gnomad EAS exome AF: 0.712

Gnomad FIN exome AF: 0.651

Gnomad NFE exome AF: 0.695

Gnomad OTH exome AF: 0.711

GnomAD4 exome AF: 0.701 AC: 1021107 AN: 1457304 Hom.: 359294 Cov.: 56 AF XY: 0.702 AC XY: 508675 AN XY: 724836

African (AFR) AF: 0.474 AC: 15824 AN: 33408

American (AMR) AF: 0.796 AC: 35318 AN: 44370

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 18023 AN: 26086

East Asian (EAS) AF: 0.729 AC: 28842 AN: 39580

South Asian (SAS) AF: 0.738 AC: 63466 AN: 86048

European-Finnish (FIN) AF: 0.654 AC: 33950 AN: 51894

Middle Eastern (MID) AF: 0.679 AC: 3822 AN: 5628

European-Non Finnish (NFE) AF: 0.703 AC: 780660 AN: 1110080

Other (OTH) AF: 0.684 AC: 41202 AN: 60210

GnomAD4 genome AF: 0.643 AC: 97417 AN: 151554 Hom.: 31993 Cov.: 32 AF XY: 0.646 AC XY: 47826 AN XY: 74026

African (AFR) AF: 0.486 AC: 20058 AN: 41296

American (AMR) AF: 0.751 AC: 11468 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 2350 AN: 3462

East Asian (EAS) AF: 0.722 AC: 3698 AN: 5124

South Asian (SAS) AF: 0.747 AC: 3588 AN: 4806

European-Finnish (FIN) AF: 0.650 AC: 6817 AN: 10488

Middle Eastern (MID) AF: 0.658 AC: 187 AN: 284

European-Non Finnish (NFE) AF: 0.695 AC: 47106 AN: 67814

Other (OTH) AF: 0.679 AC: 1432 AN: 2108

Alfa AF: 0.659 Hom.: 6167

Bravo AF: 0.644

Asia WGS AF: 0.707 AC: 2460 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hyperprolinemia type 2 (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.091
DANN	Benign	0.72
PhyloP100		-6.1
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7550938; hg19: chr1-19202917; COSMIC: COSV51894187;