9-38396160-G-C

Variant names:

• chr9-38396160-G-C
• NM_000692.5:c.412G>C

Variant summary

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

The NM_000692.5(ALDH1B1):​c.412G>C​(p.Asp138His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALDH1B1 NM_000692.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.32

Genes affected

ALDH1B1 (HGNC:407): (aldehyde dehydrogenase 1 family member B1) This protein belongs to the aldehyde dehydrogenases family of proteins. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. This gene does not contain introns in the coding sequence. The variation of this locus may affect the development of alcohol-related problems. [provided by RefSeq, Jul 2008]

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, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1B1	NM_000692.5	c.412G>C	p.Asp138His	missense_variant	Exon 2 of 2	ENST00000377698.4	NP_000683.3
ALDH1B1	XM_011517802.3	c.553G>C	p.Asp185His	missense_variant	Exon 2 of 2		XP_011516104.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1B1	ENST00000377698.4	c.412G>C	p.Asp138His	missense_variant	Exon 2 of 2	1	NM_000692.5	ENSP00000366927.3
ALDH1B1	ENST00000635162.1	c.*22G>C		downstream_gene_variant		3		ENSP00000489053.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 97 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.412G>C (p.D138H) alteration is located in exon 2 (coding exon 1) of the ALDH1B1 gene. This alteration results from a G to C substitution at nucleotide position 412, causing the aspartic acid (D) at amino acid position 138 to be replaced by a histidine (H). 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.80	T
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Vest4		0.81
MutPred		0.80		Gain of phosphorylation at Y135 (P = 0.1236);
MVP		0.43
MPC		0.51
ClinPred		1.0	D
GERP RS		5.6
gMVP		0.83

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: chr9-38396157;