17-82433808-A-C

Position:

• chr17-82433808-A-C

Variant summary

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

The NM_001330542.2(HEXD):​c.433A>C​(p.Ile145Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I145V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HEXD NM_001330542.2 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXD	NM_001330542.2	c.433A>C	p.Ile145Leu	missense_variant	5/13	ENST00000327949.15	NP_001317471.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXD	ENST00000327949.15	c.433A>C	p.Ile145Leu	missense_variant	5/13	1	NM_001330542.2	ENSP00000332634	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245678 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133788

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1459856 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 726202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.0058	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	1.2
DANN	Benign	0.88
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.81	T;.;T;T;T
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.73	D;D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationTaster	Benign	0.99	P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N;N;.;.;.
REVEL	Uncertain	0.54
Sift	Benign	0.084	T;D;.;.;.
Sift4G	Uncertain	0.059	T;D;D;T;.
Vest4		0.38
MutPred		0.76		Loss of catalytic residue at I145 (P = 0.0322);Loss of catalytic residue at I145 (P = 0.0322);.;Loss of catalytic residue at I145 (P = 0.0322);Loss of catalytic residue at I145 (P = 0.0322);
MVP		0.57
MPC		0.28
ClinPred		0.11	T
GERP RS		0.036
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.64

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;