3-43691008-G-T

Variant names:

• chr3-43691008-G-T
• rs1553614642
• NM_016006.6:c.16G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_016006.6(ABHD5):​c.16G>T​(p.Glu6*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,418,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ABHD5 NM_016006.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.18
• Publications: 0 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: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 24 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-43691008-G-T is Pathogenic according to our data. Variant chr3-43691008-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 523800.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABHD5	NM_016006.6	MANE Select	c.16G>T	p.Glu6*	stop_gained	Exon 1 of 7	NP_057090.2
	ABHD5	NM_001355186.2		c.16G>T	p.Glu6*	stop_gained	Exon 1 of 8	NP_001342115.1	Q8WTS1
	ABHD5	NM_001365650.1		c.16G>T	p.Glu6*	stop_gained	Exon 1 of 6	NP_001352579.1	A0A2U3TZT9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABHD5	ENST00000644371.2	MANE Select	c.16G>T	p.Glu6*	stop_gained	Exon 1 of 7	ENSP00000495778.1	Q8WTS1
	ABHD5	ENST00000458276.7	TSL:1	c.16G>T	p.Glu6*	stop_gained	Exon 1 of 6	ENSP00000390849.3	A0A2U3TZT9
	ABHD5	ENST00000967519.1		c.16G>T	p.Glu6*	stop_gained	Exon 1 of 8	ENSP00000637578.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1418384 Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 2 AN XY: 705752

African (AFR) AF: 0.00 AC: 0 AN: 29358

American (AMR) AF: 0.00 AC: 0 AN: 40012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24816

East Asian (EAS) AF: 0.00 AC: 0 AN: 34474

South Asian (SAS) AF: 0.0000365 AC: 3 AN: 82126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093328

Other (OTH) AF: 0.00 AC: 0 AN: 58450

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	43
DANN	Uncertain	0.99
Eigen	Uncertain	0.26
Eigen_PC	Benign	-0.067
FATHMM_MKL	Benign	0.72	D
PhyloP100		1.2
Vest4		0.26
GERP RS		1.2
PromoterAI		-0.089	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=18/182	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: rs1553614642; hg19: chr3-43732500;