rs61749348

Variant names:

• chr1-18874494-G-A
• rs61749348
• NM_003748.4:c.1548C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-18874494-G-A
• chr1-18874494-G-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003748.4(ALDH4A1):​c.1548C>T​(p.Gly516Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,614,068 control chromosomes in the GnomAD database, including 1,434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (567 hom., cov: 34)
  • Exomes 𝑓: 0.023 (867 hom.)
• Consequence: ALDH4A1 NM_003748.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.11
• Publications: 4 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 -16 ACMG points.

• BP6: Variant 1-18874494-G-A is Benign according to our data. Variant chr1-18874494-G-A is described in ClinVar as Benign. ClinVar VariationId is 294365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 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.1548C>T	p.Gly516Gly	synonymous	Exon 14 of 15	NP_003739.2
	ALDH4A1	NM_170726.3		c.1548C>T	p.Gly516Gly	synonymous	Exon 14 of 16	NP_733844.1	P30038-1
	ALDH4A1	NM_001319218.2		c.1395C>T	p.Gly465Gly	synonymous	Exon 13 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.1548C>T	p.Gly516Gly	synonymous	Exon 14 of 15	ENSP00000364490.3	P30038-1
	ALDH4A1	ENST00000290597.9	TSL:1	c.1548C>T	p.Gly516Gly	synonymous	Exon 14 of 16	ENSP00000290597.5	P30038-1
	ALDH4A1	ENST00000538839.5	TSL:1	c.1395C>T	p.Gly465Gly	synonymous	Exon 13 of 14	ENSP00000446071.1	P30038-3

Frequencies

GnomAD3 genomes AF: 0.0603 AC: 9168 AN: 152156 Hom.: 565 Cov.: 34

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0352

Gnomad ASJ AF: 0.0397

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0210

Gnomad OTH AF: 0.0498

GnomAD2 exomes AF: 0.0298 AC: 7481 AN: 250986 AF XY: 0.0276

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.0295

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0271

Gnomad NFE exome AF: 0.0223

Gnomad OTH exome AF: 0.0336

GnomAD4 exome AF: 0.0233 AC: 34085 AN: 1461794 Hom.: 867 Cov.: 32 AF XY: 0.0228 AC XY: 16615 AN XY: 727192

African (AFR) AF: 0.165 AC: 5518 AN: 33476

American (AMR) AF: 0.0215 AC: 960 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0315 AC: 824 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0172 AC: 1483 AN: 86258

European-Finnish (FIN) AF: 0.0268 AC: 1431 AN: 53338

Middle Eastern (MID) AF: 0.0657 AC: 379 AN: 5768

European-Non Finnish (NFE) AF: 0.0194 AC: 21584 AN: 1112006

Other (OTH) AF: 0.0315 AC: 1905 AN: 60392

GnomAD4 genome AF: 0.0603 AC: 9185 AN: 152274 Hom.: 567 Cov.: 34 AF XY: 0.0582 AC XY: 4333 AN XY: 74450

African (AFR) AF: 0.159 AC: 6619 AN: 41532

American (AMR) AF: 0.0351 AC: 538 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0397 AC: 138 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0188 AC: 91 AN: 4832

European-Finnish (FIN) AF: 0.0235 AC: 250 AN: 10624

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0209 AC: 1425 AN: 68020

Other (OTH) AF: 0.0493 AC: 104 AN: 2110

Alfa AF: 0.0394 Hom.: 479

Bravo AF: 0.0659

Asia WGS AF: 0.0200 AC: 72 AN: 3478

EpiCase AF: 0.0264

EpiControl AF: 0.0253

ClinVar

ClinVar submissions

Significance: 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
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Benign	0.89
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61749348; hg19: chr1-19200988;