17-82424452-T-G

Position:

• chr17-82424452-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001330542.2(HEXD):​c.143T>G​(p.Met48Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HEXD NM_001330542.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.213

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]

HEXD (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXD	NM_001330542.2	c.143T>G	p.Met48Arg	missense_variant	3/13	ENST00000327949.15	NP_001317471.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXD	ENST00000327949.15	c.143T>G	p.Met48Arg	missense_variant	3/13	1	NM_001330542.2	ENSP00000332634.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Nov 14, 2024

The c.143T>G (p.M48R) alteration is located in exon 3 (coding exon 2) of the HEXDC gene. This alteration results from a T to G substitution at nucleotide position 143, causing the methionine (M) at amino acid position 48 to be replaced by an arginine (R). 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	0.58
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Benign	0.94
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.95	D;.;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D
MetaSVM	Uncertain	0.53	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.0	D;D;.;.;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.011	D;D;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;.;D
Vest4		0.70
MutPred		0.73		Loss of phosphorylation at Y45 (P = 0.087);Loss of phosphorylation at Y45 (P = 0.087);Loss of phosphorylation at Y45 (P = 0.087);Loss of phosphorylation at Y45 (P = 0.087);.;
MVP		0.78
MPC		0.89
ClinPred		0.99	D
GERP RS		3.8
gMVP		0.93

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: chr17-80382328;