17-82433808-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001330542.2(HEXD):c.433A>T(p.Ile145Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,459,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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 Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• 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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXD	NM_001330542.2	c.433A>T	p.Ile145Phe	missense_variant	5/13	ENST00000327949.15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXD	ENST00000327949.15	c.433A>T	p.Ile145Phe	missense_variant	5/13	1	NM_001330542.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1459856 Hom.: 0 Cov.: 36 AF XY: 0.00000551 AC XY: 4 AN XY: 726202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	13
Dann	Benign	0.38
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.93	D;.;D;D;T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationTaster	Benign	0.45	P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.9	D;D;.;.;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;D;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;.
Vest4		0.46
MutPred		0.77		Gain of methylation at R142 (P = 0.1433);Gain of methylation at R142 (P = 0.1433);.;Gain of methylation at R142 (P = 0.1433);Gain of methylation at R142 (P = 0.1433);
MVP		0.64
MPC		0.92
ClinPred		0.98	D
GERP RS		0.036
gMVP		0.85

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;