8-18071253-T-TATA

Variant names:

• chr8-18071253-T-TATA
• rs34859055
• NM_177924.5:c.216+46_216+47insTAT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_177924.5(ASAH1):​c.216+46_216+47insTAT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14855 hom., cov: 0)
  • Exomes 𝑓: 0.45 (91896 hom.)
• Consequence: ASAH1 NM_177924.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.469
• Publications: 1 publications found

Genes affected

ASAH1 (HGNC:735): (N-acylsphingosine amidohydrolase 1) This gene encodes a member of the acid ceramidase family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. Processing of this preproprotein generates alpha and beta subunits that heterodimerize to form the mature lysosomal enzyme, which catalyzes the degradation of ceramide into sphingosine and free fatty acid. This enzyme is overexpressed in multiple human cancers and may play a role in cancer progression. Mutations in this gene are associated with the lysosomal storage disorder, Farber lipogranulomatosis, and a neuromuscular disorder, spinal muscular atrophy with progressive myoclonic epilepsy. [provided by RefSeq, Oct 2015]

ASAH1 Gene-Disease associations (from GenCC):

• ASAH1-related sphingolipidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Farber lipogranulomatosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• spinal muscular atrophy-progressive myoclonic epilepsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 8-18071253-T-TATA is Benign according to our data. Variant chr8-18071253-T-TATA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_177924.5	c.216+46_216+47insTAT		intron_variant	Intron 3 of 13	ENST00000637790.2	NP_808592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2	c.216+46_216+47insTAT		intron_variant	Intron 3 of 13	1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes AF: 0.439 AC: 64715 AN: 147284 Hom.: 14839 Cov.: 0

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.584

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.625

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.532

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.439

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.477

GnomAD2 exomes AF: 0.474 AC: 32721 AN: 68998 AF XY: 0.483

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.571

Gnomad ASJ exome AF: 0.608

Gnomad EAS exome AF: 0.288

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.482

Gnomad OTH exome AF: 0.477

GnomAD4 exome AF: 0.454 AC: 388599 AN: 856834 Hom.: 91896 Cov.: 12 AF XY: 0.457 AC XY: 195960 AN XY: 428576

African (AFR) AF: 0.238 AC: 4464 AN: 18758

American (AMR) AF: 0.563 AC: 7706 AN: 13678

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 9033 AN: 15312

East Asian (EAS) AF: 0.385 AC: 10279 AN: 26676

South Asian (SAS) AF: 0.504 AC: 16362 AN: 32456

European-Finnish (FIN) AF: 0.385 AC: 10806 AN: 28086

Middle Eastern (MID) AF: 0.486 AC: 1207 AN: 2486

European-Non Finnish (NFE) AF: 0.457 AC: 312898 AN: 684296

Other (OTH) AF: 0.452 AC: 15844 AN: 35086

GnomAD4 genome AF: 0.439 AC: 64769 AN: 147392 Hom.: 14855 Cov.: 0 AF XY: 0.441 AC XY: 31691 AN XY: 71904

African (AFR) AF: 0.282 AC: 11343 AN: 40176

American (AMR) AF: 0.537 AC: 8022 AN: 14944

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 2139 AN: 3422

East Asian (EAS) AF: 0.386 AC: 1948 AN: 5044

South Asian (SAS) AF: 0.534 AC: 2514 AN: 4706

European-Finnish (FIN) AF: 0.440 AC: 4206 AN: 9560

Middle Eastern (MID) AF: 0.438 AC: 126 AN: 288

European-Non Finnish (NFE) AF: 0.497 AC: 32980 AN: 66314

Other (OTH) AF: 0.474 AC: 965 AN: 2038

Alfa AF: 0.194 Hom.: 444

Asia WGS AF: 0.413 AC: 1427 AN: 3456

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34859055; hg19: chr8-17928762;