15-57961164-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_Moderate PM2 PP3_Moderate PP5

The NM_003888.4(ALDH1A2):c.1382C>A(p.Ser461Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S461C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALDH1A2 NM_003888.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.15

Genes affected

ALDH1A2 (HGNC:15472): (aldehyde dehydrogenase 1 family member A2) This protein belongs to the aldehyde dehydrogenase family of proteins. The product of this gene is an enzyme that catalyzes the synthesis of retinoic acid (RA) from retinaldehyde. Retinoic acid, the active derivative of vitamin A (retinol), is a hormonal signaling molecule that functions in developing and adult tissues. The studies of a similar mouse gene suggest that this enzyme and the cytochrome CYP26A1, concurrently establish local embryonic retinoic acid levels which facilitate posterior organ development and prevent spina bifida. Four transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, May 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PS1: Transcript NM_003888.4 (ALDH1A2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905
• PP5: Variant 15-57961164-G-T is Pathogenic according to our data. Variant chr15-57961164-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1703737.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-57961164-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH1A2	NM_003888.4	c.1382C>A	p.Ser461Tyr	missense_variant	11/13	ENST00000249750.9
ALDH1A2	NM_001206897.2	c.1319C>A	p.Ser440Tyr	missense_variant	12/14
ALDH1A2	NM_170696.3	c.1268C>A	p.Ser423Tyr	missense_variant	10/12
ALDH1A2	NM_170697.3	c.1094C>A	p.Ser365Tyr	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH1A2	ENST00000249750.9	c.1382C>A	p.Ser461Tyr	missense_variant	11/13	1	NM_003888.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Diaphragmatic hernia 4, with cardiovascular defects Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Uncertain	0.51	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.2	D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.99, 0.95	.;D;P;.;.
Vest4		0.73
MutPred		0.79		.;Gain of ubiquitination at K456 (P = 0.1051);.;.;.;
MVP		0.83
MPC		1.3
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.94
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-58253362;