chr11-67663252-C-T

Position:

• chr11-67663252-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001393402.2(ALDH3B2):​c.1121G>A​(p.Arg374His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,613,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: ALDH3B2 NM_001393402.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.624

Genes affected

ALDH3B2 (HGNC:411): (aldehyde dehydrogenase 3 family member B2) This gene encodes a member of the aldehyde dehydrogenase family, a group of isozymes that may play a major role in the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation. The gene of this particular family member is over 10 kb in length. Altered methylation patterns at this locus have been observed in spermatozoa derived from patients exhibiting reduced fecundity. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09203324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH3B2	NM_001393402.2	c.1121G>A	p.Arg374His	missense_variant	10/10	ENST00000673966.2	NP_001380331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH3B2	ENST00000673966.2	c.1121G>A	p.Arg374His	missense_variant	10/10		NM_001393402.2	ENSP00000501254.1
ALDH3B2	ENST00000530069.6	c.1121G>A	p.Arg374His	missense_variant	10/10	1		ENSP00000431595.1
ALDH3B2	ENST00000349015.7	c.1121G>A	p.Arg374His	missense_variant	10/10	5		ENSP00000255084.3
ALDH3B2	ENST00000531248.1	c.306G>A	p.Thr102Thr	synonymous_variant	3/3	5		ENSP00000435476.1

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152210 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000240 AC: 60 AN: 250004 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 135066

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.000503

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.000209 AC: 305 AN: 1460810 Hom.: 0 Cov.: 32 AF XY: 0.000187 AC XY: 136 AN XY: 726684

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000605

Gnomad4 ASJ exome AF: 0.000538

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000190

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152210 Hom.: 0 Cov.: 34 AF XY: 0.000188 AC XY: 14 AN XY: 74348

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.000200 Hom.: 0

Bravo AF: 0.000336

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000273

EpiControl AF: 0.000356

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

Oct 06, 2021

The c.1121G>A (p.R374H) alteration is located in exon 10 (coding exon 8) of the ALDH3B2 gene. This alteration results from a G to A substitution at nucleotide position 1121, causing the arginine (R) at amino acid position 374 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	Benign	0.10
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.6
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.28	.;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.092	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.25
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.024	D;D
Polyphen		0.98	D;D
Vest4		0.042
MVP		0.79
MPC		0.24
ClinPred		0.062	T
GERP RS		-3.2
Varity_R		0.036
gMVP		0.62

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: rs140105486; hg19: chr11-67430723;