19-49461796-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_153329.4(ALDH16A1):c.755C>T(p.Pro252Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,610,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P252R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: ALDH16A1 NM_153329.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.729

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_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04359579).
• BP6: Variant 19-49461796-C-T is Benign according to our data. Variant chr19-49461796-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2620580.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH16A1	NM_153329.4	c.755C>T	p.Pro252Leu	missense_variant	6/17	ENST00000293350.9
ALDH16A1	NM_001145396.2	c.755C>T	p.Pro252Leu	missense_variant	6/16
ALDH16A1	XM_011526441.1	c.668C>T	p.Pro223Leu	missense_variant	6/17
ALDH16A1	XM_047438163.1	c.668C>T	p.Pro223Leu	missense_variant	7/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH16A1	ENST00000293350.9	c.755C>T	p.Pro252Leu	missense_variant	6/17	1	NM_153329.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152114 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000333 AC: 8 AN: 240374 Hom.: 0 AF XY: 0.0000229 AC XY: 3 AN XY: 131086

Gnomad AFR exome AF: 0.000266

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000373

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1458392 Hom.: 0 Cov.: 59 AF XY: 0.0000152 AC XY: 11 AN XY: 725394

Gnomad4 AFR exome AF: 0.0000899

Gnomad4 AMR exome AF: 0.0000225

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: 0.0000225

Gnomad4 OTH exome AF: 0.0000831

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152114 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74290

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000153 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	17
Dann	Benign	0.94
DEOGEN2	Benign	0.075	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.17	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.044	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.50	N;.;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.65	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.058	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.084
MVP		0.29
MPC		0.072
ClinPred		0.042	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.042
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs776704156; hg19: chr19-49965053;