3-43691003-A-G

Variant names:

• chr3-43691003-A-G
• rs138400599
• NM_016006.6:c.11A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016006.6(ABHD5):​c.11A>G​(p.Glu4Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,410,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E4A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ABHD5 NM_016006.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.239
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1007013).

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.11A>G	p.Glu4Gly	missense	Exon 1 of 7	NP_057090.2
	ABHD5	NM_001355186.2		c.11A>G	p.Glu4Gly	missense	Exon 1 of 8	NP_001342115.1	Q8WTS1
	ABHD5	NM_001365650.1		c.11A>G	p.Glu4Gly	missense	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.11A>G	p.Glu4Gly	missense	Exon 1 of 7	ENSP00000495778.1	Q8WTS1
	ABHD5	ENST00000458276.7	TSL:1	c.11A>G	p.Glu4Gly	missense	Exon 1 of 6	ENSP00000390849.3	A0A2U3TZT9
	ABHD5	ENST00000967519.1		c.11A>G	p.Glu4Gly	missense	Exon 1 of 8	ENSP00000637578.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410102 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 701280

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29248

American (AMR) AF: 0.00 AC: 0 AN: 39400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24612

East Asian (EAS) AF: 0.00 AC: 0 AN: 34214

South Asian (SAS) AF: 0.00 AC: 0 AN: 81182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1088896

Other (OTH) AF: 0.00 AC: 0 AN: 58086

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.47	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.24
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.35
Sift	Benign	0.26	T
Sift4G	Benign	0.15	T
Polyphen		0.028	B
Vest4		0.46
MutPred		0.17		Gain of loop (P = 0.0121)
MVP		0.70
MPC		0.17
ClinPred		0.22	T
GERP RS		1.8
PromoterAI		0.079	Neutral
Varity_R		0.060
gMVP		0.43
Mutation Taster		=89/11	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: rs138400599; hg19: chr3-43732495;