17-82433808-A-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• 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: Likely_pathogenic. The variant received 6 ACMG points.

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

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>T	p.Ile145Phe	missense	Exon 5 of 13	NP_001317471.1	Q8WVB3-1
	HEXD	NM_173620.3		c.433A>T	p.Ile145Phe	missense	Exon 5 of 12	NP_775891.2	Q8WVB3-2
	HEXD	NM_001369487.1		c.157A>T	p.Ile53Phe	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>T	p.Ile145Phe	missense	Exon 5 of 13	ENSP00000332634.9	Q8WVB3-1
	HEXD	ENST00000337014.10	TSL:1	c.433A>T	p.Ile145Phe	missense	Exon 5 of 12	ENSP00000337854.6	Q8WVB3-2
	HEXD	ENST00000577944.5	TSL:5	c.433A>T	p.Ile145Phe	missense	Exon 5 of 13	ENSP00000463129.1	J3QKL0

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

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 86048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111372

Other (OTH) AF: 0.00 AC: 0 AN: 60338

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.84	D
PhyloP100		0.080
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Vest4		0.46
MutPred		0.77		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
Mutation Taster		=56/44	polymorphism

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;