NM_000520.6:c.116T>G

Variant names:

• chr15-72375857-A-C
• rs121907979
• NM_000520.6:c.116T>G

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.116T>G​(p.Leu39Arg) variant causes a missense change. 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 Affects (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L39F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HEXA NM_000520.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided O:1
• Conservation: PhyloP100: 4.27
• Publications: 3 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]

ENSG00000260729 (HGNC:):

HEXA-AS1 (HGNC:25810): (HEXA antisense RNA 1)

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, 20 uncertain in NM_000520.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6	c.116T>G	p.Leu39Arg	missense_variant	Exon 1 of 14	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.116T>G	p.Leu39Arg	missense_variant	Exon 1 of 14		NP_001305754.1
HEXA	NR_134869.3	n.158T>G		non_coding_transcript_exon_variant	Exon 1 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.116T>G	p.Leu39Arg	missense_variant	Exon 1 of 14	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.116T>G		non_coding_transcript_exon_variant	Exon 1 of 16	2		ENSP00000478716.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Tay-Sachs disease Other:1

Jan 01, 1993

OMIM

Significance: Affects

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.9	M;.;.;.
PhyloP100		4.3
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-4.5	D;D;D;.
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.63
MutPred		0.98		Gain of disorder (P = 0.0457);Gain of disorder (P = 0.0457);Gain of disorder (P = 0.0457);Gain of disorder (P = 0.0457);
MVP		0.97
MPC		0.91
ClinPred		0.99	D
GERP RS		4.7
PromoterAI		-0.071	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.92
Mutation Taster		=18/82	disease causing (ClinVar)

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: rs121907979; hg19: chr15-72668198;