rs2230705

Variant names:

• chr1-18877503-C-G
• rs2230705
• NM_003748.4:c.1050G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-18877503-C-G
• chr1-18877503-C-A
• chr1-18877503-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003748.4(ALDH4A1):​c.1050G>C​(p.Ala350Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,607,222 control chromosomes in the GnomAD database, including 408,905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38646 hom., cov: 33)
  • Exomes 𝑓: 0.71 (370259 hom.)
• Consequence: ALDH4A1 NM_003748.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.60
• Publications: 21 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=-0.43).
• BP6: Variant 1-18877503-C-G is Benign according to our data. Variant chr1-18877503-C-G is described in ClinVar as Benign. ClinVar VariationId is 294382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.6 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 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.1050G>C	p.Ala350Ala	synonymous	Exon 10 of 15	NP_003739.2
	ALDH4A1	NM_170726.3		c.1050G>C	p.Ala350Ala	synonymous	Exon 10 of 16	NP_733844.1	P30038-1
	ALDH4A1	NM_001319218.2		c.1050G>C	p.Ala350Ala	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.1050G>C	p.Ala350Ala	synonymous	Exon 10 of 15	ENSP00000364490.3	P30038-1
	ALDH4A1	ENST00000290597.9	TSL:1	c.1050G>C	p.Ala350Ala	synonymous	Exon 10 of 16	ENSP00000290597.5	P30038-1
	ALDH4A1	ENST00000538839.5	TSL:1	c.1050G>C	p.Ala350Ala	synonymous	Exon 10 of 14	ENSP00000446071.1	P30038-3

Frequencies

GnomAD3 genomes AF: 0.710 AC: 107923 AN: 152036 Hom.: 38609 Cov.: 33

Gnomad AFR AF: 0.722

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.718

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.807

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.720

Gnomad OTH AF: 0.696

GnomAD2 exomes AF: 0.689 AC: 164889 AN: 239156 AF XY: 0.683

Gnomad AFR exome AF: 0.723

Gnomad AMR exome AF: 0.746

Gnomad ASJ exome AF: 0.619

Gnomad EAS exome AF: 0.449

Gnomad FIN exome AF: 0.801

Gnomad NFE exome AF: 0.719

Gnomad OTH exome AF: 0.700

GnomAD4 exome AF: 0.710 AC: 1033651 AN: 1455068 Hom.: 370259 Cov.: 76 AF XY: 0.706 AC XY: 510376 AN XY: 723282

African (AFR) AF: 0.724 AC: 24183 AN: 33402

American (AMR) AF: 0.744 AC: 32685 AN: 43910

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 16226 AN: 26004

East Asian (EAS) AF: 0.456 AC: 17993 AN: 39478

South Asian (SAS) AF: 0.588 AC: 50128 AN: 85278

European-Finnish (FIN) AF: 0.799 AC: 41602 AN: 52066

Middle Eastern (MID) AF: 0.596 AC: 3329 AN: 5586

European-Non Finnish (NFE) AF: 0.727 AC: 806171 AN: 1109242

Other (OTH) AF: 0.688 AC: 41334 AN: 60102

GnomAD4 genome AF: 0.710 AC: 108017 AN: 152154 Hom.: 38646 Cov.: 33 AF XY: 0.711 AC XY: 52891 AN XY: 74388

African (AFR) AF: 0.721 AC: 29937 AN: 41500

American (AMR) AF: 0.718 AC: 10986 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 2219 AN: 3470

East Asian (EAS) AF: 0.456 AC: 2356 AN: 5166

South Asian (SAS) AF: 0.582 AC: 2810 AN: 4830

European-Finnish (FIN) AF: 0.807 AC: 8566 AN: 10612

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.719 AC: 48900 AN: 67964

Other (OTH) AF: 0.691 AC: 1460 AN: 2112

Alfa AF: 0.693 Hom.: 9493

Bravo AF: 0.705

Asia WGS AF: 0.520 AC: 1813 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hyperprolinemia type 2 (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.7
DANN	Benign	0.74
PhyloP100		1.6
Mutation Taster		=97/3	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: rs2230705; hg19: chr1-19203997; COSMIC: COSV51892136;