chr3-43691032-GGA-G

Variant names:

• chr3-43691032-GGA-G
• rs387906336
• ENST00000644371.2:c.35_36delAG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_016006.6(ABHD5):​c.46_47delAG​(p.Arg16ValfsTer20) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,408,460 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ABHD5 NM_016006.6 frameshift, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.0570
• Publications: 1 publications found

Genes affected

ABHD5 (HGNC:21396): (abhydrolase domain containing 5, lysophosphatidic acid acyltransferase) The protein encoded by this gene belongs to a large family of proteins defined by an alpha/beta hydrolase fold, and contains three sequence motifs that correspond to a catalytic triad found in the esterase/lipase/thioesterase subfamily. It differs from other members of this subfamily in that its putative catalytic triad contains an asparagine instead of the serine residue. Mutations in this gene have been associated with Chanarin-Dorfman syndrome, a triglyceride storage disease with impaired long-chain fatty acid oxidation. [provided by RefSeq, Jul 2008]

ANO10 (HGNC:25519): (anoctamin 10) The transmembrane protein encoded by this gene belongs to the anoctamin family of calcium-activated chloride channels, also known as the transmembrane 16 family. The encoded protein contains eight transmembrane domains with cytosolic N- and C-termini. Defects in this gene may cause autosomal recessive spinocerebellar ataxia-10. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

ANO10 Gene-Disease associations (from GenCC):

• autosomal recessive spinocerebellar ataxia 10

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 23 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-43691032-GGA-G is Pathogenic according to our data. Variant chr3-43691032-GGA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 5354.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016006.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABHD5	NM_016006.6	MANE Select	c.46_47delAG	p.Arg16ValfsTer20	frameshift splice_region	Exon 1 of 7	NP_057090.2
	ABHD5	NM_001355186.2		c.46_47delAG	p.Arg16ValfsTer20	frameshift splice_region	Exon 1 of 8	NP_001342115.1
	ABHD5	NM_001365650.1		c.46_47delAG	p.Arg16ValfsTer20	frameshift splice_region	Exon 1 of 6	NP_001352579.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABHD5	ENST00000644371.2	MANE Select	c.35_36delAG	p.Thr13ValfsTer20	frameshift	Exon 1 of 7	ENSP00000495778.1
	ABHD5	ENST00000458276.7	TSL:1	c.35_36delAG	p.Thr13ValfsTer20	frameshift	Exon 1 of 6	ENSP00000390849.3
	ABHD5	ENST00000967519.1		c.35_36delAG	p.Thr13ValfsTer20	frameshift	Exon 1 of 8	ENSP00000637578.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1408460 Hom.: 0 AF XY: 0.00000143 AC XY: 1 AN XY: 700670

African (AFR) AF: 0.00 AC: 0 AN: 29072

American (AMR) AF: 0.00 AC: 0 AN: 38594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24560

East Asian (EAS) AF: 0.00 AC: 0 AN: 33418

South Asian (SAS) AF: 0.00 AC: 0 AN: 81168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1087644

Other (OTH) AF: 0.00 AC: 0 AN: 57914

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Triglyceride storage disease with ichthyosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.057
Mutation Taster		=17/183	disease causing (ClinVar)

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: rs387906336; hg19: chr3-43732524;