NM_000520.6:c.1195A>G

Variant names:

• chr15-72346662-T-C
• rs1800430
• NM_000520.6:c.1195A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000520.6(HEXA):​c.1195A>G​(p.Asn399Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00732 in 1,614,028 control chromosomes in the GnomAD database, including 451 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N399S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.031 (213 hom., cov: 30)
  • Exomes 𝑓: 0.0048 (238 hom.)
• Consequence: HEXA NM_000520.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.18
• Publications: 15 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

CELF6-AS1 (HGNC:58304):

ENSG00000260729 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000520.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0056626797).
• BP6: Variant 15-72346662-T-C is Benign according to our data. Variant chr15-72346662-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

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.1195A>G	p.Asn399Asp	missense	Exon 11 of 14	NP_000511.2	P06865-1
	HEXA	NM_001318825.2		c.1228A>G	p.Asn410Asp	missense	Exon 11 of 14	NP_001305754.1	H3BP20
	HEXA	NR_134869.3		n.1116-337A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.1195A>G	p.Asn399Asp	missense	Exon 11 of 14	ENSP00000268097.6	P06865-1
	HEXA	ENST00000567159.5	TSL:1	c.1195A>G	p.Asn399Asp	missense	Exon 11 of 13	ENSP00000456489.1	H3BS10
	CELF6-AS1	ENST00000570175.1	TSL:1	n.1442T>C		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4734 AN: 152114 Hom.: 213 Cov.: 30

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.0264

GnomAD2 exomes AF: 0.00909 AC: 2287 AN: 251478 AF XY: 0.00711

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.00847

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00199

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00484 AC: 7075 AN: 1461796 Hom.: 238 Cov.: 34 AF XY: 0.00442 AC XY: 3214 AN XY: 727200

African (AFR) AF: 0.107 AC: 3596 AN: 33460

American (AMR) AF: 0.00906 AC: 405 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000823 AC: 71 AN: 86254

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53418

Middle Eastern (MID) AF: 0.00662 AC: 38 AN: 5736

European-Non Finnish (NFE) AF: 0.00215 AC: 2391 AN: 1111986

Other (OTH) AF: 0.00881 AC: 532 AN: 60386

GnomAD4 genome AF: 0.0311 AC: 4737 AN: 152232 Hom.: 213 Cov.: 30 AF XY: 0.0302 AC XY: 2251 AN XY: 74438

African (AFR) AF: 0.105 AC: 4347 AN: 41524

American (AMR) AF: 0.0123 AC: 188 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00207 AC: 141 AN: 68022

Other (OTH) AF: 0.0261 AC: 55 AN: 2108

Alfa AF: 0.0130 Hom.: 254

Bravo AF: 0.0353

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.103 AC: 453

ESP6500EA AF: 0.00175 AC: 15

ExAC AF: 0.0110 AC: 1331

Asia WGS AF: 0.00577 AC: 21 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00231

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	Tay-Sachs disease (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	3.8
DANN	Benign	0.60
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.14	N
PhyloP100		-1.2
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.27
Sift	Benign	0.47	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.20
MPC		0.21
ClinPred		0.0017	T
GERP RS		-12
Varity_R		0.068
gMVP		0.58
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1800430; hg19: chr15-72639003;