rs72953172

Variant names:

• chr1-18872906-G-A
• rs72953172
• NM_003748.4:c.1631C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-18872906-G-A
• chr1-18872906-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003748.4(ALDH4A1):​c.1631C>T​(p.Pro544Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,614,072 control chromosomes in the GnomAD database, including 79 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. P544P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (41 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (38 hom.)
• Consequence: ALDH4A1 NM_003748.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.74
• 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: 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 (MetaRNN=0.0097464025).
• BP6: Variant 1-18872906-G-A is Benign according to our data. Variant chr1-18872906-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 294364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0126 (1921/152292) while in subpopulation AFR AF = 0.0419 (1741/41548). AF 95% confidence interval is 0.0403. There are 41 homozygotes in GnomAd4. There are 894 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 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.1631C>T	p.Pro544Leu	missense	Exon 15 of 15	NP_003739.2
	ALDH4A1	NM_170726.3		c.1631C>T	p.Pro544Leu	missense	Exon 15 of 16	NP_733844.1
	ALDH4A1	NM_001319218.2		c.1478C>T	p.Pro493Leu	missense	Exon 14 of 14	NP_001306147.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH4A1	ENST00000375341.8	TSL:1 MANE Select	c.1631C>T	p.Pro544Leu	missense	Exon 15 of 15	ENSP00000364490.3
	ALDH4A1	ENST00000290597.9	TSL:1	c.1631C>T	p.Pro544Leu	missense	Exon 15 of 16	ENSP00000290597.5
	ALDH4A1	ENST00000538839.5	TSL:1	c.1478C>T	p.Pro493Leu	missense	Exon 14 of 14	ENSP00000446071.1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1917 AN: 152174 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00968

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00330 AC: 829 AN: 251366 AF XY: 0.00232

Gnomad AFR exome AF: 0.0429

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00128 AC: 1870 AN: 1461780 Hom.: 38 Cov.: 31 AF XY: 0.00109 AC XY: 791 AN XY: 727190

African (AFR) AF: 0.0415 AC: 1389 AN: 33480

American (AMR) AF: 0.00318 AC: 142 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.000133 AC: 148 AN: 1112000

Other (OTH) AF: 0.00283 AC: 171 AN: 60396

GnomAD4 genome AF: 0.0126 AC: 1921 AN: 152292 Hom.: 41 Cov.: 33 AF XY: 0.0120 AC XY: 894 AN XY: 74484

African (AFR) AF: 0.0419 AC: 1741 AN: 41548

American (AMR) AF: 0.00967 AC: 148 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68024

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00674 Hom.: 23

Bravo AF: 0.0145

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0399 AC: 176

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00394 AC: 479

Asia WGS AF: 0.00375 AC: 14 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

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
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		9.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.055	T
Polyphen		0.89	P
Vest4		0.84
MVP		0.92
MPC		0.52
ClinPred		0.12	T
GERP RS		4.8
Varity_R		0.58
gMVP		0.74
Mutation Taster		=42/58	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72953172; hg19: chr1-19199400; COSMIC: COSV106408062;