rs11740

Variant names:

• chr1-18872727-C-T
• rs11740
• NM_003748.4:c.*118G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-18872727-C-T
• chr1-18872727-C-A
• chr1-18872727-C-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.*118G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 767,614 control chromosomes in the GnomAD database, including 78,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13051 hom., cov: 32)
  • Exomes 𝑓: 0.45 (65384 hom.)
• Consequence: ALDH4A1 NM_003748.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.797
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-18872727-C-T is Benign according to our data. Variant chr1-18872727-C-T is described in ClinVar as Benign. ClinVar VariationId is 294359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.654 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.*118G>A		3_prime_UTR	Exon 15 of 15	NP_003739.2
	ALDH4A1	NM_001319218.2		c.*118G>A		3_prime_UTR	Exon 14 of 14	NP_001306147.1	P30038-3
	ALDH4A1	NM_001161504.2		c.*118G>A		3_prime_UTR	Exon 15 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.*118G>A		3_prime_UTR	Exon 15 of 15	ENSP00000364490.3	P30038-1
	ALDH4A1	ENST00000538839.5	TSL:1	c.*118G>A		3_prime_UTR	Exon 14 of 14	ENSP00000446071.1	P30038-3
	ALDH4A1	ENST00000290597.9	TSL:1	c.*41+77G>A		intron	N/A	ENSP00000290597.5	P30038-1

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60633 AN: 151812 Hom.: 13035 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.673

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.422

GnomAD4 exome AF: 0.453 AC: 278636 AN: 615686 Hom.: 65384 Cov.: 8 AF XY: 0.458 AC XY: 149282 AN XY: 325912

African (AFR) AF: 0.236 AC: 3964 AN: 16816

American (AMR) AF: 0.575 AC: 19523 AN: 33924

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 7063 AN: 16464

East Asian (EAS) AF: 0.663 AC: 23380 AN: 35268

South Asian (SAS) AF: 0.571 AC: 32995 AN: 57750

European-Finnish (FIN) AF: 0.414 AC: 14807 AN: 35758

Middle Eastern (MID) AF: 0.409 AC: 962 AN: 2352

European-Non Finnish (NFE) AF: 0.420 AC: 162002 AN: 385544

Other (OTH) AF: 0.438 AC: 13940 AN: 31810

GnomAD4 genome AF: 0.399 AC: 60679 AN: 151928 Hom.: 13051 Cov.: 32 AF XY: 0.408 AC XY: 30316 AN XY: 74228

African (AFR) AF: 0.246 AC: 10210 AN: 41446

American (AMR) AF: 0.524 AC: 8013 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 1419 AN: 3468

East Asian (EAS) AF: 0.673 AC: 3468 AN: 5152

South Asian (SAS) AF: 0.593 AC: 2848 AN: 4804

European-Finnish (FIN) AF: 0.418 AC: 4409 AN: 10544

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.426 AC: 28925 AN: 67920

Other (OTH) AF: 0.421 AC: 888 AN: 2110

Alfa AF: 0.424 Hom.: 15945

Bravo AF: 0.399

Asia WGS AF: 0.594 AC: 2064 AN: 3478

ClinVar

ClinVar submissions

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	-0.90
CADD	Benign	0.60
DANN	Benign	0.43
PhyloP100		-0.80
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: rs11740; hg19: chr1-19199221; COSMIC: COSV51892981; COSMIC: COSV51892981;