17-82433808-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 43 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330542.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXD	NM_001330542.2	MANE Select	c.433A>G	p.Ile145Val	missense	Exon 5 of 13	NP_001317471.1	Q8WVB3-1
	HEXD	NM_173620.3		c.433A>G	p.Ile145Val	missense	Exon 5 of 12	NP_775891.2	Q8WVB3-2
	HEXD	NM_001369487.1		c.157A>G	p.Ile53Val	missense	Exon 6 of 15	NP_001356416.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXD	ENST00000327949.15	TSL:1 MANE Select	c.433A>G	p.Ile145Val	missense	Exon 5 of 13	ENSP00000332634.9	Q8WVB3-1
	HEXD	ENST00000337014.10	TSL:1	c.433A>G	p.Ile145Val	missense	Exon 5 of 12	ENSP00000337854.6	Q8WVB3-2
	HEXD	ENST00000577944.5	TSL:5	c.433A>G	p.Ile145Val	missense	Exon 5 of 13	ENSP00000463129.1	J3QKL0

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

GnomAD2 exomes AF: 0.450 AC: 110502 AN: 245678 AF XY: 0.434

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 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

African (AFR) AF: 0.503 AC: 16781 AN: 33358

American (AMR) AF: 0.662 AC: 29491 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 9950 AN: 26086

East Asian (EAS) AF: 0.914 AC: 36155 AN: 39554

South Asian (SAS) AF: 0.430 AC: 37028 AN: 86016

European-Finnish (FIN) AF: 0.328 AC: 17275 AN: 52720

Middle Eastern (MID) AF: 0.364 AC: 2096 AN: 5758

European-Non Finnish (NFE) AF: 0.333 AC: 369764 AN: 1110996

Other (OTH) AF: 0.399 AC: 24087 AN: 60326

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

African (AFR) AF: 0.496 AC: 20596 AN: 41534

American (AMR) AF: 0.565 AC: 8634 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1331 AN: 3468

East Asian (EAS) AF: 0.909 AC: 4703 AN: 5174

South Asian (SAS) AF: 0.438 AC: 2117 AN: 4828

European-Finnish (FIN) AF: 0.326 AC: 3455 AN: 10600

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.337 AC: 22879 AN: 67974

Other (OTH) AF: 0.459 AC: 971 AN: 2114

Alfa AF: 0.382 Hom.: 34978

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0000049	T
MetaSVM	Benign	-0.96	T
PhyloP100		0.080
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.65	N
REVEL	Uncertain	0.33
Sift	Benign	0.28	T
Sift4G	Benign	0.35	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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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