15-72346551-T-C

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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:15
• Conservation: PhyloP100: -0.152

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 93189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72346551-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXA	NM_000520.6	c.1306A>G	p.Ile436Val	missense_variant	11/14	ENST00000268097.10
HEXA	NM_001318825.2	c.1339A>G	p.Ile447Val	missense_variant	11/14
HEXA	NR_134869.3	n.1116-226A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXA	ENST00000268097.10	c.1306A>G	p.Ile436Val	missense_variant	11/14	1	NM_000520.6	P1
	ENST00000570175.1	n.1331T>C		non_coding_transcript_exon_variant	2/3	1

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

GnomAD3 exomes AF: 0.970 AC: 243905 AN: 251366 Hom.: 119523 AF XY: 0.979 AC XY: 132973 AN XY: 135884

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 SAS exome AF: 0.998

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

Gnomad4 AFR exome AF: 0.599

Gnomad4 AMR exome AF: 0.979

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.998

Gnomad4 FIN exome AF: 0.998

Gnomad4 NFE exome AF: 0.999

Gnomad4 OTH exome AF: 0.975

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

Gnomad4 AFR AF: 0.613

Gnomad4 AMR AF: 0.962

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.998

Gnomad4 FIN AF: 0.997

Gnomad4 NFE AF: 0.998

Gnomad4 OTH AF: 0.920

Alfa AF: 0.978 Hom.: 112495

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

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 22, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Tay-Sachs disease Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

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;.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.034	T;T;T
MetaRNN	Benign	0.0000013	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.090	N;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.67	N;N;N
REVEL	Benign	0.23
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.28	T;T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800431; hg19: chr15-72638892;