19-49460893-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_153329.4(ALDH16A1):c.571G>T(p.Ala191Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ALDH16A1 NM_153329.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.91

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH16A1	NM_153329.4	c.571G>T	p.Ala191Ser	missense_variant	5/17	ENST00000293350.9
ALDH16A1	NM_001145396.2	c.571G>T	p.Ala191Ser	missense_variant	5/16
ALDH16A1	XM_011526441.1	c.484G>T	p.Ala162Ser	missense_variant	5/17
ALDH16A1	XM_047438163.1	c.484G>T	p.Ala162Ser	missense_variant	6/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH16A1	ENST00000293350.9	c.571G>T	p.Ala191Ser	missense_variant	5/17	1	NM_153329.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Jul 19, 2023

The c.571G>T (p.A191S) alteration is located in exon 5 (coding exon 5) of the ALDH16A1 gene. This alteration results from a G to T substitution at nucleotide position 571, causing the alanine (A) at amino acid position 191 to be replaced by a serine (S). 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	0.16
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;D;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.1	M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0080	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.34	B;P;.
Vest4		0.72
MutPred		0.91		Gain of helix (P = 0.2684);.;Gain of helix (P = 0.2684);
MVP		0.84
MPC		0.23
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr19-49964150;