15-72346551-T-C

Variant names:

• chr15-72346551-T-C
• rs1800431
• NM_000520.6:c.1306A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000520.6(HEXA):​c.1306A>G​(p.Ile436Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.978 in 1,613,876 control chromosomes in the GnomAD database, including 778,194 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I436L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.89 (62308 hom., cov: 31)
  • Exomes 𝑓: 0.99 (715886 hom.)
• Consequence: HEXA NM_000520.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.152
• Publications: 50 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2768097E-6).
• BP6: Variant 15-72346551-T-C is Benign according to our data. Variant chr15-72346551-T-C is described in ClinVar as Benign. ClinVar VariationId is 93189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 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.1306A>G	p.Ile436Val	missense	Exon 11 of 14	NP_000511.2	P06865-1
	HEXA	NM_001318825.2		c.1339A>G	p.Ile447Val	missense	Exon 11 of 14	NP_001305754.1	H3BP20
	HEXA	NR_134869.3		n.1116-226A>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.1306A>G	p.Ile436Val	missense	Exon 11 of 14	ENSP00000268097.6	P06865-1
	HEXA	ENST00000567159.5	TSL:1	c.1306A>G	p.Ile436Val	missense	Exon 11 of 13	ENSP00000456489.1	H3BS10
	CELF6-AS1	ENST00000570175.1	TSL:1	n.1331T>C		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.889 AC: 135134 AN: 152046 Hom.: 62290 Cov.: 31

Gnomad AFR AF: 0.613

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.962

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.998

Gnomad FIN AF: 0.997

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.919

GnomAD2 exomes AF: 0.970 AC: 243905 AN: 251366 AF XY: 0.979

Gnomad AFR exome AF: 0.604

Gnomad AMR exome AF: 0.981

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.998

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.987

GnomAD4 exome AF: 0.988 AC: 1443888 AN: 1461712 Hom.: 715886 Cov.: 55 AF XY: 0.989 AC XY: 719363 AN XY: 727168

African (AFR) AF: 0.599 AC: 20047 AN: 33464

American (AMR) AF: 0.979 AC: 43765 AN: 44724

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26129 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39693 AN: 39698

South Asian (SAS) AF: 0.998 AC: 86080 AN: 86250

European-Finnish (FIN) AF: 0.998 AC: 53313 AN: 53420

Middle Eastern (MID) AF: 0.970 AC: 5550 AN: 5722

European-Non Finnish (NFE) AF: 0.999 AC: 1110466 AN: 1111914

Other (OTH) AF: 0.975 AC: 58845 AN: 60384

GnomAD4 genome AF: 0.889 AC: 135203 AN: 152164 Hom.: 62308 Cov.: 31 AF XY: 0.892 AC XY: 66352 AN XY: 74394

African (AFR) AF: 0.613 AC: 25398 AN: 41446

American (AMR) AF: 0.962 AC: 14715 AN: 15300

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3471 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5159 AN: 5162

South Asian (SAS) AF: 0.998 AC: 4816 AN: 4826

European-Finnish (FIN) AF: 0.997 AC: 10588 AN: 10618

Middle Eastern (MID) AF: 0.976 AC: 287 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67912 AN: 68020

Other (OTH) AF: 0.920 AC: 1945 AN: 2114

Alfa AF: 0.959 Hom.: 149220

Bravo AF: 0.872

TwinsUK AF: 0.998 AC: 3702

ALSPAC AF: 0.999 AC: 3849

ESP6500AA AF: 0.620 AC: 2726

ESP6500EA AF: 0.998 AC: 8577

ExAC AF: 0.964 AC: 117031

Asia WGS AF: 0.976 AC: 3394 AN: 3478

EpiCase AF: 0.997

EpiControl AF: 0.997

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	5	Tay-Sachs disease (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	2.5
DANN	Benign	0.76
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.034	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.090	N
PhyloP100		-0.15
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.67	N
REVEL	Benign	0.23
Sift	Benign	0.24	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.029
MPC		0.16
ClinPred		0.0049	T
GERP RS		-7.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.017
gMVP		0.63
Mutation Taster		=96/4	polymorphism (auto)

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: rs1800431; hg19: chr15-72638892; COSMIC: COSV107268201; COSMIC: COSV107268201;