rs34085965

Variant names:

• chr15-72346318-A-G
• rs34085965
• NM_000520.6:c.1338T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-72346318-A-G
• chr15-72346318-A-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000520.6(HEXA):​c.1338T>C​(p.Pro446Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000349 in 1,613,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P446P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: HEXA NM_000520.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.967
• 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]

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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 15-72346318-A-G is Benign according to our data. Variant chr15-72346318-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 695932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.967 with no splicing effect.

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.1338T>C	p.Pro446Pro	synonymous	Exon 12 of 14	NP_000511.2	P06865-1
	HEXA	NM_001318825.2		c.1371T>C	p.Pro457Pro	synonymous	Exon 12 of 14	NP_001305754.1	H3BP20
	HEXA	NR_134869.3		n.1123T>C		non_coding_transcript_exon	Exon 10 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.1338T>C	p.Pro446Pro	synonymous	Exon 12 of 14	ENSP00000268097.6	P06865-1
	HEXA	ENST00000567159.5	TSL:1	c.1338T>C	p.Pro446Pro	synonymous	Exon 12 of 13	ENSP00000456489.1	H3BS10
	ENSG00000260729	ENST00000379915.4	TSL:2	n.420T>C		non_coding_transcript_exon	Exon 4 of 16	ENSP00000478716.1	A0A087WUJ7

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000251 AC: 63 AN: 250932 AF XY: 0.000265

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000458

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000356 AC: 520 AN: 1461348 Hom.: 0 Cov.: 30 AF XY: 0.000359 AC XY: 261 AN XY: 726990

African (AFR) AF: 0.0000598 AC: 2 AN: 33460

American (AMR) AF: 0.0000895 AC: 4 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.000281 AC: 15 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000435 AC: 484 AN: 1111600

Other (OTH) AF: 0.000248 AC: 15 AN: 60384

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74476

African (AFR) AF: 0.000168 AC: 7 AN: 41550

American (AMR) AF: 0.000588 AC: 9 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000447 Hom.: 0

Bravo AF: 0.000363

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Tay-Sachs disease (2)
-	-	1	HEXA-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.3
DANN	Benign	0.84
PhyloP100		-0.97
Mutation Taster		=106/94	polymorphism

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: rs34085965; hg19: chr15-72638659; COSMIC: COSV99173648; COSMIC: COSV99173648;