chr15-72348118-T-A

Variant names:

• chr15-72348118-T-A
• rs1555472604
• NM_000520.6:c.1003A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000520.6(HEXA):​c.1003A>T​(p.Ile335Phe) 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. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HEXA NM_000520.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.553
• Publications: 1 publications found

Genes affected

HEXA (HGNC:4878): (hexosaminidase subunit alpha) This gene encodes a member of the glycosyl hydrolase 20 family of proteins. The encoded preproprotein is proteolytically processed to generate the alpha subunit of the lysosomal enzyme beta-hexosaminidase. This enzyme, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene lead to an accumulation of GM2 ganglioside in neurons, the underlying cause of neurodegenerative disorders termed the GM2 gangliosidoses, including Tay-Sachs disease (GM2-gangliosidosis type I). Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

HEXA Gene-Disease associations (from GenCC):

• Tay-Sachs disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ENSG00000260729 (HGNC:):

CELF6-AS1 (HGNC:58304):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000520.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000520.6. 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
	HEXA	NM_000520.6	MANE Select	c.1003A>T	p.Ile335Phe	missense	Exon 9 of 14	NP_000511.2	P06865-1
	HEXA	NM_001318825.2		c.1036A>T	p.Ile346Phe	missense	Exon 9 of 14	NP_001305754.1	H3BP20
	HEXA	NR_134869.3		n.1045A>T		non_coding_transcript_exon	Exon 9 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.1003A>T	p.Ile335Phe	missense	Exon 9 of 14	ENSP00000268097.6	P06865-1
	HEXA	ENST00000567159.5	TSL:1	c.1003A>T	p.Ile335Phe	missense	Exon 9 of 13	ENSP00000456489.1	H3BS10
	ENSG00000260729	ENST00000379915.4	TSL:2	n.413-1793A>T		intron	N/A	ENSP00000478716.1	A0A087WUJ7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Tay-Sachs disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.97	D
Eigen	Benign	0.17
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		0.55
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.66	P
Vest4		0.84
MutPred		0.95		Gain of ubiquitination at K330 (P = 0.0741)
MVP		0.98
MPC		0.85
ClinPred		1.0	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.89
Mutation Taster		=3/97	disease causing

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: rs1555472604; hg19: chr15-72640459;