rs35657817

Variant names:

• chr1-18874401-C-G
• rs35657817
• NM_003748.4:c.1579+62G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-18874401-C-G
• chr1-18874401-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003748.4(ALDH4A1):​c.1579+62G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALDH4A1 NM_003748.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.1579+62G>C		intron_variant	Intron 14 of 14	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.1579+62G>C		intron_variant	Intron 14 of 15		NP_733844.1
ALDH4A1	NM_001319218.2	c.1426+62G>C		intron_variant	Intron 13 of 13		NP_001306147.1
ALDH4A1	NM_001161504.2	c.1399+62G>C		intron_variant	Intron 14 of 14		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1579+62G>C		intron_variant	Intron 14 of 14	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9	c.1579+62G>C		intron_variant	Intron 14 of 15	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5	c.1426+62G>C		intron_variant	Intron 13 of 13	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5	c.1399+62G>C		intron_variant	Intron 14 of 14	2		ENSP00000442988.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1316234 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 660440

African (AFR) AF: 0.00 AC: 0 AN: 30296

American (AMR) AF: 0.00 AC: 0 AN: 44276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25076

East Asian (EAS) AF: 0.00 AC: 0 AN: 38824

South Asian (SAS) AF: 0.00 AC: 0 AN: 83188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48644

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5520

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 984828

Other (OTH) AF: 0.00 AC: 0 AN: 55582

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 745

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.019
DANN	Benign	0.32
PhyloP100		-1.0

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: rs35657817; hg19: chr1-19200895;