19-49453356-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_153329.4(ALDH16A1):c.25C>A(p.Arg9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,551,554 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 (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

ALDH16A1
NM_153329.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.248

Variant links:

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]

ALDH16A1 links:

PIH1D1 (HGNC:26075): (PIH1 domain containing 1) Enables several functions, including RNA polymerase I core promoter sequence-specific DNA binding activity; enzyme binding activity; and phosphoprotein binding activity. Involved in several processes, including box C/D snoRNP assembly; positive regulation of signal transduction; and regulation of cellular protein metabolic process. Located in cytoplasm and nucleolus. Part of R2TP complex and pre-snoRNP complex. [provided by Alliance of Genome Resources, Apr 2022]

PIH1D1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.01044935).

BP6

Variant 19-49453356-C-A is Benign according to our data. Variant chr19-49453356-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2595842.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ALDH16A1	NM_153329.4 linkuse as main transcript	c.25C>A	p.Arg9Ser	missense_variant	1/17	ENST00000293350.9
ALDH16A1	NM_001145396.2 linkuse as main transcript	c.25C>A	p.Arg9Ser	missense_variant	1/16
ALDH16A1	XM_047438163.1 linkuse as main transcript	c.-174C>A		5_prime_UTR_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH16A1	ENST00000293350.9 linkuse as main transcript	c.25C>A	p.Arg9Ser	missense_variant	1/17	1	NM_153329.4	P1	Q8IZ83-1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

143024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000104

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:

0.000403

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000185

AC:

AN:

183664

Hom.:

AF XY:

0.000220

AC XY:

AN XY:

99976

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000695

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000839

Gnomad NFE exome

AF:

0.000392

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000240

AC:

338

AN:

1408406

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

163

AN XY:

697620

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000507

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000229

Gnomad4 NFE exome

AF:

0.000302

Gnomad4 OTH exome

AF:

0.000120

GnomAD4 genome

AF:

0.000210

AC:

AN:

143148

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

AN XY:

70026

show subpopulations

Gnomad4 AFR

AF:

0.000104

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:

0.000403

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000367

Hom.:

Bravo

AF:

0.000212

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000469

AC:

ExAC

AF:

0.000135

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 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

0.12

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.50

Cadd

Benign

3.2

Dann

Benign

0.92

DEOGEN2

Benign

0.00023

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.58

T;T

M_CAP

Benign

0.0091

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.1

N;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

0.67

N;N

REVEL

Benign

0.053

Sift

Benign

1.0

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.0010

B;.

Vest4

0.068

MVP

0.13

MPC

0.080

ClinPred

0.034

GERP RS

-4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.057

gMVP

0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over