17-82433808-A-G

Variant names:

• chr17-82433808-A-G
• rs4789773
• NM_001330542.2:c.433A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001330542.2(HEXD):​c.433A>G​(p.Ile145Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,611,518 control chromosomes in the GnomAD database, including 126,366 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.43 (15296 hom., cov: 33)
  • Exomes 𝑓: 0.37 (111070 hom.)
• Consequence: HEXD NM_001330542.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0800

Genes affected

HEXD (HGNC:26307): (hexosaminidase D) Enables beta-N-acetylhexosaminidase activity. Predicted to be involved in carbohydrate metabolic process. Located in extracellular vesicle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.8481857E-6).
• BP6: Variant 17-82433808-A-G is Benign according to our data. Variant chr17-82433808-A-G is described in ClinVar as [Benign]. Clinvar id is 402933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXD	NM_001330542.2	c.433A>G	p.Ile145Val	missense_variant	Exon 5 of 13	ENST00000327949.15	NP_001317471.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXD	ENST00000327949.15	c.433A>G	p.Ile145Val	missense_variant	Exon 5 of 13	1	NM_001330542.2	ENSP00000332634.9

Frequencies

GnomAD3 genomes AF: 0.428 AC: 65123 AN: 152064 Hom.: 15255 Cov.: 33

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.909

Gnomad SAS AF: 0.440

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.454

GnomAD3 exomes AF: 0.450 AC: 110502 AN: 245678 Hom.: 28939 AF XY: 0.434 AC XY: 58025 AN XY: 133788

Gnomad AFR exome AF: 0.499

Gnomad AMR exome AF: 0.679

Gnomad ASJ exome AF: 0.383

Gnomad EAS exome AF: 0.915

Gnomad SAS exome AF: 0.432

Gnomad FIN exome AF: 0.320

Gnomad NFE exome AF: 0.336

Gnomad OTH exome AF: 0.421

GnomAD4 exome AF: 0.372 AC: 542627 AN: 1459336 Hom.: 111070 Cov.: 36 AF XY: 0.371 AC XY: 269402 AN XY: 725982

Gnomad4 AFR exome AF: 0.503

Gnomad4 AMR exome AF: 0.662

Gnomad4 ASJ exome AF: 0.381

Gnomad4 EAS exome AF: 0.914

Gnomad4 SAS exome AF: 0.430

Gnomad4 FIN exome AF: 0.328

Gnomad4 NFE exome AF: 0.333

Gnomad4 OTH exome AF: 0.399

GnomAD4 genome AF: 0.429 AC: 65216 AN: 152182 Hom.: 15296 Cov.: 33 AF XY: 0.433 AC XY: 32186 AN XY: 74400

Gnomad4 AFR AF: 0.496

Gnomad4 AMR AF: 0.565

Gnomad4 ASJ AF: 0.384

Gnomad4 EAS AF: 0.909

Gnomad4 SAS AF: 0.438

Gnomad4 FIN AF: 0.326

Gnomad4 NFE AF: 0.337

Gnomad4 OTH AF: 0.459

Alfa AF: 0.371 Hom.: 22295

Bravo AF: 0.455

TwinsUK AF: 0.326 AC: 1209

ALSPAC AF: 0.330 AC: 1271

ESP6500AA AF: 0.474 AC: 1839

ESP6500EA AF: 0.338 AC: 2796

ExAC AF: 0.438 AC: 52917

Asia WGS AF: 0.658 AC: 2285 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.13
DANN	Benign	0.38
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.62	T;.;T;T;T
MetaRNN	Benign	0.0000048	T;T;T;T;T
MetaSVM	Benign	-0.96	T
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.65	N;N;.;.;.
REVEL	Uncertain	0.33
Sift	Benign	0.28	T;T;.;.;.
Sift4G	Benign	0.35	T;T;T;T;.
Vest4		0.18
MPC		0.23
ClinPred		0.0032	T
GERP RS		0.036
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.38

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: rs4789773; hg19: chr17-80391684; COSMIC: COSV60064130; COSMIC: COSV60064130;