rs6426813

Variant names:

• chr1-18877660-G-A
• rs6426813
• NM_003748.4:c.941-48C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-18877660-G-A
• chr1-18877660-G-T

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.941-48C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.734 in 1,384,948 control chromosomes in the GnomAD database, including 376,492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (40377 hom., cov: 33)
  • Exomes 𝑓: 0.74 (336115 hom.)
• Consequence: ALDH4A1 NM_003748.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.839
• Publications: 6 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 (BayesDel_noAF=-0.91).
• BP6: Variant 1-18877660-G-A is Benign according to our data. Variant chr1-18877660-G-A is described in ClinVar as [Benign]. Clinvar id is 1188873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.933 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.941-48C>T		intron_variant	Intron 9 of 14	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.941-48C>T		intron_variant	Intron 9 of 15		NP_733844.1
ALDH4A1	NM_001319218.2	c.941-48C>T		intron_variant	Intron 9 of 13		NP_001306147.1
ALDH4A1	NM_001161504.2	c.761-48C>T		intron_variant	Intron 9 of 14		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.941-48C>T		intron_variant	Intron 9 of 14	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9	c.941-48C>T		intron_variant	Intron 9 of 15	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5	c.941-48C>T		intron_variant	Intron 9 of 13	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5	c.761-48C>T		intron_variant	Intron 9 of 14	2		ENSP00000442988.1

Frequencies

GnomAD3 genomes AF: 0.724 AC: 110064 AN: 151962 Hom.: 40352 Cov.: 33

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.849

Gnomad AMR AF: 0.823

Gnomad ASJ AF: 0.804

Gnomad EAS AF: 0.956

Gnomad SAS AF: 0.856

Gnomad FIN AF: 0.619

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.699

Gnomad OTH AF: 0.749

GnomAD2 exomes AF: 0.770 AC: 165590 AN: 215114 AF XY: 0.767

Gnomad AFR exome AF: 0.696

Gnomad AMR exome AF: 0.886

Gnomad ASJ exome AF: 0.810

Gnomad EAS exome AF: 0.954

Gnomad FIN exome AF: 0.636

Gnomad NFE exome AF: 0.707

Gnomad OTH exome AF: 0.779

GnomAD4 exome AF: 0.735 AC: 906548 AN: 1232868 Hom.: 336115 Cov.: 25 AF XY: 0.738 AC XY: 457695 AN XY: 620536

African (AFR) AF: 0.701 AC: 20453 AN: 29158

American (AMR) AF: 0.879 AC: 37168 AN: 42280

Ashkenazi Jewish (ASJ) AF: 0.806 AC: 19774 AN: 24524

East Asian (EAS) AF: 0.955 AC: 36697 AN: 38422

South Asian (SAS) AF: 0.838 AC: 67364 AN: 80346

European-Finnish (FIN) AF: 0.634 AC: 31012 AN: 48880

Middle Eastern (MID) AF: 0.831 AC: 3096 AN: 3726

European-Non Finnish (NFE) AF: 0.714 AC: 651548 AN: 912786

Other (OTH) AF: 0.748 AC: 39436 AN: 52746

GnomAD4 genome AF: 0.724 AC: 110145 AN: 152080 Hom.: 40377 Cov.: 33 AF XY: 0.726 AC XY: 53997 AN XY: 74346

African (AFR) AF: 0.700 AC: 29021 AN: 41472

American (AMR) AF: 0.824 AC: 12613 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.804 AC: 2791 AN: 3470

East Asian (EAS) AF: 0.955 AC: 4917 AN: 5148

South Asian (SAS) AF: 0.855 AC: 4127 AN: 4828

European-Finnish (FIN) AF: 0.619 AC: 6537 AN: 10562

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.699 AC: 47535 AN: 67972

Other (OTH) AF: 0.746 AC: 1576 AN: 2112

Alfa AF: 0.690 Hom.: 6982

Bravo AF: 0.739

Asia WGS AF: 0.886 AC: 3079 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperprolinemia type 2 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.4
DANN	Benign	0.79
PhyloP100		-0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs6426813; hg19: chr1-19204154;