19-49458535-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153329.4(ALDH16A1):c.140A>G(p.Lys47Arg) variant causes a missense 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALDH16A1 NM_153329.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.370

Genes affected

ALDH16A1 (HGNC:28114): (aldehyde dehydrogenase 16 family member A1) This gene encodes a member of the aldehyde dehydrogenase superfamily. The family members act on aldehyde substrates and use nicotinamide adenine dinucleotide phosphate (NADP) as a cofactor. This gene is conserved in chimpanzee, dog, cow, mouse, rat, and zebrafish. The protein encoded by this gene interacts with maspardin, a protein that when truncated is responsible for Mast syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16979).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH16A1	NM_153329.4	c.140A>G	p.Lys47Arg	missense_variant	2/17	ENST00000293350.9
ALDH16A1	NM_001145396.2	c.140A>G	p.Lys47Arg	missense_variant	2/16
ALDH16A1	XM_011526441.1	c.53A>G	p.Lys18Arg	missense_variant	2/17
ALDH16A1	XM_047438163.1	c.53A>G	p.Lys18Arg	missense_variant	3/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH16A1	ENST00000293350.9	c.140A>G	p.Lys47Arg	missense_variant	2/17	1	NM_153329.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1415546 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 699752

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

The c.140A>G (p.K47R) alteration is located in exon 2 (coding exon 2) of the ALDH16A1 gene. This alteration results from a A to G substitution at nucleotide position 140, causing the lysine (K) at amino acid position 47 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0024	T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.95	N;N
REVEL	Benign	0.023
Sift	Benign	0.47	T;T
Sift4G	Benign	0.073	T;T
Polyphen		0.43	B;.
Vest4		0.10
MutPred		0.35		Loss of methylation at K47 (P = 0.0084);Loss of methylation at K47 (P = 0.0084);
MVP		0.17
MPC		0.060
ClinPred		0.15	T
GERP RS		1.3
Varity_R		0.039
gMVP		0.24

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-49961792;